estrogen: what is its place today? february, 2010 ruth freeman md albert einstein college of...
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Estrogen: What is its place Estrogen: What is its place today?today?
February, 2010February, 2010
Ruth Freeman MDRuth Freeman MDAlbert Einstein College of Albert Einstein College of
MedicineMedicine
Menopausal TransitionMenopausal Transition
Perimenopause Menopause Postmenopause
3-4 years before menopause
Actual cessation of menses
one year after Last period
1/3 of lifetimeIrregular menses Onset of symptoms Age 40 - 58
Mean age 50.5FSH ↑ day 1-2
Of period. E2 normal.
Inhibin B
FSH and E2 variable elevated to low.
Inhibin lower
FSH high, E2 low
Inhibin absent
Effect of estrogen variation in early Effect of estrogen variation in early postmenopausal periodpostmenopausal period
HOT HOT FlushesFlushes (power surges) (power surges)
change in body ‘thermostat’.change in body ‘thermostat’.
To cool body:To cool body:
increase skin blood flowincrease skin blood flow
sweatingsweating
increased blood flow to skinincreased blood flow to skin
Years Before Years After
Menopause
Prevalence of Hot Flushes
3 2 1 1 2 3
Prevalence of Hot FlushesPrevalence of Hot Flushes >75% of women report hot flushes within the 2-year >75% of women report hot flushes within the 2-year
period around menopauseperiod around menopause Primary reason women seek medical treatmentPrimary reason women seek medical treatment 25% remain symptomatic for >5 years25% remain symptomatic for >5 years
Kronenberg F. Kronenberg F. Ann NY Acad SciAnn NY Acad Sci. 1990;592:52-86. . 1990;592:52-86. Kronenberg F. Kronenberg F. Ann NY Acad SciAnn NY Acad Sci. 1990;592:52-86. . 1990;592:52-86.
0
5
10
15
20
25
30
35
40
45
50
Years
Nu
mb
er o
f S
ub
ject
s
Number of years women report having Number of years women report having hot flushes as estimated by a survey of hot flushes as estimated by a survey of 501 501 self-selected women who experienced self-selected women who experienced hot flusheshot flushes
Mean age of natural menopause was 49.5 years; mean age of surgical menopause was 43.7 years.Mean age of natural menopause was 49.5 years; mean age of surgical menopause was 43.7 years.
Kronenberg F. Kronenberg F. Ann NY Acad SciAnn NY Acad Sci. 1990;592:52-86. . 1990;592:52-86.
Mean age of natural menopause was 49.5 years; mean age of surgical menopause was 43.7 years.Mean age of natural menopause was 49.5 years; mean age of surgical menopause was 43.7 years.
Kronenberg F. Kronenberg F. Ann NY Acad SciAnn NY Acad Sci. 1990;592:52-86. . 1990;592:52-86.
Hot Flushes May Continue Hot Flushes May Continue Years After MenopauseYears After Menopause
0 2 4 6 8 10 12 14 16 18 20 22 24 28 30 36 41
Ages 29 to 82 Years
Management:Management:1)1) Lifestyle changes, cool environment Lifestyle changes, cool environment
2)2) Vitamin E, Phytoestrogens, dong quai, and Vitamin E, Phytoestrogens, dong quai, and black cohoshblack cohosh——no difference compared no difference compared with placebowith placebo
3)3) Clonidine (patch or pill)Clonidine (patch or pill)
4)4) Megestrol (synthetic progestin)Megestrol (synthetic progestin)
5)5) SSRI/SNRI therapy (Zoloft,Effexor)SSRI/SNRI therapy (Zoloft,Effexor)
6)6) Gabapentin 900mg/day (Neurontin)Gabapentin 900mg/day (Neurontin)
Week
Mea
n H
ot
Flu
sh S
core
(%
of
bas
elin
e)
Weekly Hot Flush Scores for Breast Cancer Patients in a Randomized Crossover Study
No significant difference was found between treatment groups at any week.Quella SK, et al. J Clin Oncol. 2000;18:1068-74.
Effect of Soy in Reducing Hot Flushes Effect of Soy in Reducing Hot Flushes Is Similar to PlaceboIs Similar to Placebo
0.0
0.2
0.4
0.6
0.8
1.0
1 2 3 4 5 6 7 8 9
Soy
Soy
Placebo
Placebo
**0
2
4
6
8
10
12
14
-4 0 6 11 16 21 26
Treatment Daysn = 7; treatment was CEE 0.625 mg for 27 days.*P < .01 compared with baseline.Scharf MB, et al. Clin Ther. 1997;19:304-11.
Effect of ET on Sleep QualityEffect of ET on Sleep Quality M
ea
n N
um
ber
of
Oc
cu
rre
nc
es
Mean Number of Hot Flushes per 24 Hours
Mean Number of Hot Flushes With Awakenings per Night
Ages 45 to 60 Years
Available estrogen and Available estrogen and estrogen/progestin estrogen/progestin
preparationspreparationsPills – Pills – PremarinPremarin, Estradiol, ethinyl , Estradiol, ethinyl
estradiol conjugated estrogens etc. estradiol conjugated estrogens etc. Patches – weekly, bi-weekly, combined Patches – weekly, bi-weekly, combined
with progesterone.with progesterone.Creams and gels – applied to skin dailyCreams and gels – applied to skin daily Injectibles – estradiol depot or Injectibles – estradiol depot or
enanthate monthly enanthate monthly For listing go to menopause.org (NAMS For listing go to menopause.org (NAMS
website)website)
First Pass Hepatic Effects of First Pass Hepatic Effects of Estrogens Taken by MouthEstrogens Taken by Mouth
IntestineIntestine
LiverLiver
Oral Oral EstrogenEstrogen
Clotting FactorsClotting FactorsInflammatory Factors (CRP)Inflammatory Factors (CRP)
SteroidSteroidMetabolitesMetabolites
EstradiolEstradiolPatchPatch
SystemicCirculation
SkinSkin
OvaryOvary
Postmenopausal PeriodPostmenopausal Period
Starts one year after the last Starts one year after the last menstrual period.menstrual period.
No more bleedingNo more bleedingHormonally Hormonally FSHFSH↑ ↑ and Estradiol Estradiol ↓↓ Symptoms of estrogen deficiency ensue
Vasomotor symptoms
– Hot flashes – Sleep
disturbance
Cardiovascular disease
Urogenital atrophy
Osteoporosis
Skin dryness and aging
Brain
Eye
Vasomotor
Heart
Breast
ColonUrogenital Tract
Bone
Consequences of Estrogen Consequences of Estrogen Loss Loss
on Target Tissueon Target Tissue
Booher DL. Cleve Clin J Med. 1990;57:154-160.
A Short History of HRTA Short History of HRT
0
10
20
30
40
1960 1965 1970 1975 1980 1985 1990 1995 2003
PROGESTIN
ESTROGEN
Progestins protect endometrium
Estrogens lower CHD risk
Estrogens prevent bone loss Estrogens cause
breast cancer
benefit vs. risk
Oral contraceptives cause vascular diseases
Failed estrogens Trials in men
Estrogens cause endometrial cancer
“Feminine forever”
Prescriptions (Millions)
WHI
Unopposed Estrogen therapyUnopposed Estrogen therapy
Results in continuous stimulation of Results in continuous stimulation of the endometriumthe endometriumEndometrial hyperplasiaEndometrial hyperplasiaEndometrial carcinomaEndometrial carcinoma
Endometrial Hyperplasia Endometrial Hyperplasia Rates Rates
With Various Doses of NETAWith Various Doses of NETA
0
2
4
6
8
10
12
14
16
Hyp
erpl
asia
Rat
e A
fter
12 M
onth
s (%
)
Kurman et al. Obstet Gynecol. 2000;96:373-379.
E2 1 mg E2 1 mg/NETA 0.1 mg
E2 1 mg/NETA 0.25 mg
E2 1 mg/NETA 0.5 mg*
N = 1,176.P < .001 for all continuous-combined groups vs unopposed E2.*E2 1 mg/NETA 0.5 mg is the currently approved regimen in the U.S.
0
2
4
6
8
10
Hyp
erp
lasi
a R
ate
Aft
er 1
2 M
on
ths
(%)
[95%
Co
nfi
den
ce In
terv
al]
Treatment Groups
0.625 mg(n = 249)
0.625 mg/2.5 mg(n = 278)
PlaceboCEE CEE/MPA
Pickar et al. Fertil Steril. 2001;76:25-31.
[4.98-12.13]
*[0.00-1.32] [0.00-1.40]
Endometrial Protection With CEE/MPA
The Women’s HOPE Study The Women’s HOPE Study
**PP < .001 vs CEE alone. < .001 vs CEE alone.
(n = 261)
Prevent Endometrial Prevent Endometrial hyperplasia and possibly hyperplasia and possibly
enometrial cancer.enometrial cancer. Use progeststional agent at least 50% Use progeststional agent at least 50%
of time of the estrogens. (Cyclic)of time of the estrogens. (Cyclic)Use progestational agent all the time Use progestational agent all the time
together with estrogens all the time together with estrogens all the time (continuous)(continuous)
Every 2 – 3 months (no RCT) Every 2 – 3 months (no RCT)
Preparations MPA, progesterone, Preparations MPA, progesterone, norethindrone etc. norethindrone etc.
n = 1,426.Pouilles JM, et al. J Bone Miner Res. 1994;9:311-15.
n = 1,426.Pouilles JM, et al. J Bone Miner Res. 1994;9:311-15.
Spinal BMD by Age and Spinal BMD by Age and Menopausal StatusMenopausal Status
0.8
0.9
1.0
1.1
50 55 60 65 70
BM
D (
g/c
m2)
Perimenopausal
Menopausal for4 yrs
Menopausal for5-14 yrs Menopausal
for 15 yrs
Mean Age (years)
Lindsay R. Lancet. 1976;1:1038-41.
Met
acar
pal
Bo
ne
Min
eral
Co
nte
nt
(mg
/mm
)
Blue area represents placebo-treated population of oophorectomized women.
Years
From oophorectomy
From 3 years after oophorectomy
From 6 years after oophorectomy
44
42
40
38
36
34
0 2 4 6 8 10 12 14 16
Effect of Delayed Initiation Effect of Delayed Initiation of ERT on Bone Lossof ERT on Bone Loss
WHI – Incidence of new WHI – Incidence of new FracturesFractures
ESTROGEN/MPAESTROGEN/MPA Total 733 (8.6%)Total 733 (8.6%)
HIP – 52HIP – 52 Wrist/arm 189Wrist/arm 189 Clinical vertebral Clinical vertebral
4141
PLACEBOPLACEBO Total 896 Total 896
(11.1%)(11.1%) Hip – 73Hip – 73 Wrist/arm 245Wrist/arm 245 Clinical Vertebral Clinical Vertebral
- 60- 60
HR 0.67 (0.47-0.96)
33%reduction
Fracture Prevention: Fracture Prevention: Role of Drug TherapyRole of Drug Therapy
Hormone therapy Hormone therapy (estrogen or estrogen/progestin)(estrogen or estrogen/progestin)
Raloxifene ( a tissue specific estrogen)Raloxifene ( a tissue specific estrogen) BisphosphonatesBisphosphonates
AlendronateAlendronate RisedronateRisedronate IbandronateIbandronate zolendronatezolendronate
CalcitoninCalcitonin
denosumabdenosumab
ALL Cause mortality (per ALL Cause mortality (per 1000/yr)1000/yr)
Bush et alBush et al JAMA 1983;249:904,JAMA 1983;249:904,
Hysterectomy status Nonuser EstrogenUser
Total
Intact 9.0 (6.5-12)
4.9 (1.8-10.7)
8.2(6.1-10.8)
Hysterectomy 8.2(3.3-16.8)
2.8(0.3-10)
5.7(2.6-10.8)
Ovariectomy 11.8(5.9-21.2)
1.4(0.0-7.6
7.2(3.7-12.6)
Total 9.3(7.2-11.9)
3.4(1.5-6.4)
0.6 0.6
2.0
3.6
2.2
3.64.0
6.5
0
1
2
3
4
5
6
7
<40 40-44 45-49 50-54
Premenopausal
Postmenopausal
Incidence of Cardiovascular Incidence of Cardiovascular Disease: Relation to Disease: Relation to Menopause StatusMenopause Status
Inci
den
ce
(p
er
1,0
00 w
om
en
)
Age (years)
Kannel W, et al. Ann Intern Med. 1976;85:447-52.
Effects of estrogen Effects of estrogen deficiencydeficiency on on heart disease risk factorsheart disease risk factors
Cholesterol increasesCholesterol increases blood pressure risesblood pressure rises Vasodilation is reducedVasodilation is reduced Oxidative stress increaseOxidative stress increase Body composition less muscleBody composition less muscle Fat distribution mainly abdomenFat distribution mainly abdomen
Observational Studies of CVD Risk Observational Studies of CVD Risk and ERT/HRTand ERT/HRT
0 0.5 1.0 2.0 10
Stampfer et al (1985)
Wilson et al (1985)
Bush et al (1987)
Petitti et al (1987)
Boysen et al (1988)
Criqui et al (1988)
Henderson et al (1988)
Wolfe et al (1991)
Falkeborn et al (1992)
Psaty et al (1994)
Folsom et al (1995)
Sellers et al (1997)
Relative Risk (95% CI)
Estrogen Effects on Risk Estrogen Effects on Risk factors for Coronary artery factors for Coronary artery
diseasediseaseLipid effectsLipid effectsVasodilatationVasodilatationAntioxidantAntioxidant Improves CHO metabolismImproves CHO metabolismLowers BPLowers BP
Effects of ERT/HRT on LipidsEffects of ERT/HRT on Lipids
-15
-12
-9
-6
-3
0
3
6
9
12
15
HDL LDL Triglycerides
% C
ha
ng
e F
rom
Ba
se
lin
e
PlaceboCEECEE + MPA (cyc)CEE + MPA (con)CEE + MP (cyc)
The Writing Group for the PEPI Trial. JAMA. 1995;273:199-208.
Relative changes after 3 years of treatment.CEE = conjugated equine estrogens (0.625 mg/d); CEE + MPA (cyc) = CEE + cyclic medroxyprogesterone acetate(10 mg for 12 d/mo); CEE + MPA (con) = CEE + continuous MPA (2.5 mg/d); CEE + MP = CEE + cyclic micronized progestin (200 mg for 10 d/mo).
PEPI Trial
0.0
0.5
1.0
1.5
2.0
2.5
3.0
*P = .006 vs. placebo; no differences were observed between ERT/HRT groups.con = continuous regimen; cyc = cyclic regimen (progestin first 12 days of each cycle).Espeland MA, et al. J Clin Endocrinol Metab. 1997;82:1549-56.
Wei
gh
t C
han
ge
(kg
)
Placebo CEE0.625 mg
CEE/MPA (con)0.625 mg/2.5 mg
CEE/MPA (cyc)0.625 mg/10 mg
CEE/MP (cyc)0.625 mg/200 µg
PEPI Trial
Body Weight Changes After 3 Body Weight Changes After 3 yrs. of Treatment with HRTyrs. of Treatment with HRT
**
**
**
**
-16
-12
-8
-4
0
4Placebo Estradiol
Pe
rce
nt
Ch
an
ge
fr
om
Bas
elin
e
P = .03
P = .03
P = .009
Estrogen Effects on Glucose, Estrogen Effects on Glucose, Insulin, and HbAInsulin, and HbA1c1c
Estrogen in the Prevention of Atherosclerosis Trial (EPAT)
Fasting Glucose Fasting Insulin HbA1c
Hodis HN, et al. Ann Intern Med. 2001;135:939-53.
Effect of Menopausal Hormone Effect of Menopausal Hormone therapy (MHT) on Carbohydrate therapy (MHT) on Carbohydrate
metabolismmetabolism
HERS trial 35% less incidence of HERS trial 35% less incidence of diabetes in 4 years of MHT treatmentdiabetes in 4 years of MHT treatment
WHI – in women (mean age 64) WHI – in women (mean age 64) taking MHT for 5 years – 33% less taking MHT for 5 years – 33% less new diabetes. new diabetes.
0.5
1.0
1.5
2.0
2.5
3.0
0 12 36
Cushman M, et al. Circulation. 1999;100:717-22.
Mea
n C
-Rea
ctiv
e P
rote
in (
mg
/L)
ERT/HRT and C-Reactive ERT/HRT and C-Reactive Protein: Effect of Different Protein: Effect of Different
RegimensRegimens
Time (months)
PEPI Study: Oral ERT/HRT in Healthy Postmenopausal Women
P < .001
Placebo
CEECEE + MP
CEE + MPA cycCEE + MPA con
4.0
4.2
4.4
4.6
4.8
5.0
5.2
Baseline 6 months
Med
ian
i
n C
-Rea
ctiv
e P
rote
in (
mg
/L) Transdermal
Estradiol/NETAP = .026
PlaceboP = NS
n = 16
Transdermal HRT inDiabetic Postmenopausal Women
Time (months)NETA = norethisterone acetate.Sattar N, et al. Lancet [Res Lett]. 1999;354:487-8.
n = 365
20
30
40
50
60
Year 1 Year 2 Year 3 Year 4 + 5
Nu
mb
er
of
No
nfa
tal
MIs
or
CH
D D
ea
ths
Placebo
HRT
YearYear RHRH 95% CI95% CI
11 1.521.52 1.01–2.291.01–2.29
22 1.001.00 0.67–1.490.67–1.49
33 0.870.87 0.55–1.370.55–1.37
4 + 54 + 5 0.670.67 0.43–1.040.43–1.04
HERS
Effect of HRT vs Placebo on CHD Effect of HRT vs Placebo on CHD Events in Women With Established Events in Women With Established
Coronary DiseaseCoronary Disease
*P = .009 for trend in log RH over time.Hulley S, et al. JAMA. 1998;280:605-13.
*
WHI -Coronary artery disease WHI -Coronary artery disease events:events:
Incidence in the 5.2 yearsIncidence in the 5.2 years
8506 women 8506 women randomized to randomized to CE/MPACE/MPA CAD event 37/10,000 CAD event 37/10,000
women/yearwomen/year
HR= 1.29 (1.02-HR= 1.29 (1.02-1.631.63))
Stroke = 29/10,000/yrStroke = 29/10,000/yr
HR 1.41 (1.07-1.85HR 1.41 (1.07-1.85))
8102 on 8102 on PLACEBOPLACEBO
CAD 30/10,000 CAD 30/10,000 women/yearwomen/year
Stroke – Stroke – 21/10,000/yr21/10,000/yr
FIG. 1
Multivariable odds of a coronary calcium score >0 for Multivariable odds of a coronary calcium score >0 for oophorectomy stratified by prior hormone therapy oophorectomy stratified by prior hormone therapy
group (except those with percutaneous transluminal group (except those with percutaneous transluminal coronary angioplasty or coronary artery bypass coronary angioplasty or coronary artery bypass
grafting). *grafting). *PP < 0.01; < 0.01; † †PP
Risks and Benefits of Active and Risks and Benefits of Active and Inactive (placebo) PillsInactive (placebo) Pills
Disease rates for women on estrogen plus progestin or placebo
0
10
20
30
40
50
60
Heart
Attacks
Str
oke
s
Bre
ast
Cancer
Blo
od
Clo
ts
Colo
recta
l
Cancer
Hip
Fra
ctu
res
Endom
etr
ial
Cancer
Death
sNo
. o
f c
as
es
pe
r ye
ar
in 1
0,0
00
wo
me
n
E+P Placebo
Risk Benefit Neutral
Neurotransmission
Neuroprotection
Neurite BranchingSynaptogenesis
Cerebral Blood Flow
Trophic Factor
Expression
Effects of Estrogen on Neuronal Function
Adapted from Birge SJ. Menopause Management. 2000;July/August:13-21.
Effects of Estrogen on Brain Function
Physiologic Effects– Neuronal
protection
– Brain activation
– Cerebral blood flow
Memory Function
Mood Sleep
Alzheimer’s Disease
Estrogen
Number of Women With Event
HERS
Fatal strokeFatal stroke
Nonfatal strokeNonfatal stroke
TIATIA
Ischemic strokeIschemic stroke
Any stroke or TIAAny stroke or TIA
1.61 (0.73-3.55)1.61 (0.73-3.55)
1.18 (0.83-1.66)1.18 (0.83-1.66)
0.90 (0.57-1.42)0.90 (0.57-1.42)
1.18 (0.83-1.67)1.18 (0.83-1.67)
1.09 (0.84-1.43)1.09 (0.84-1.43)
1616
7070
3535
6969
112112
Outcome RH (95% CI)CEE/MPA
1010
6060
4444
5959
103103
Placebo
Simon JA, et al. Circulation. 2001;103:638-42.
TIA = transient ischemic attack; CEE = conjugated equine estrogens (0.625 mg/d); MPA = medroxyprogesterone acetate (2.5 mg/d); RH = relative hazard.
Risk for Stroke with HRT vs PlaceboRisk for Stroke with HRT vs Placebo
NSNS
NSNS
NSNS
NSNS
NSNS
Significance
What are the Effects of What are the Effects of estrogen therapy on estrogen therapy on
breast cancer?breast cancer?
0
0.01
0.02
0.03
0 1 2 3 4 5 6 7
Time (year)
Cu
mu
lati
ve
Ha
zard
fo
r In
va
siv
e B
rea
st
Ca
nc
er
HR = 1.26
95% nCI = 1.00–1.59 95% aCI = 0.83–1.92
WHI Results: Effect of CEE/MPAWHI Results: Effect of CEE/MPA on Risk of Invasive Breast on Risk of Invasive Breast
CancerCancer
Placebo
CEE/MPA
n (CEE/MPA) =
n (Placebo) =
8506
8102
8378
8001
8277
7891
8150
7772
7000
6619
4234
3922
2064
1740
801
523
Kaplan-Meier Estimate
Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.
Risks and Benefits of Active and Risks and Benefits of Active and Inactive (placebo) PillsInactive (placebo) Pills
Disease rates for women on estrogen plus progestin or placebo
0
10
20
30
40
50
60
Heart
Attacks
Str
oke
s
Bre
ast
Cancer
Blo
od
Clo
ts
Colo
recta
l
Cancer
Hip
Fra
ctu
res
Endom
etr
ial
Cancer
Death
sNo
. o
f c
as
es
pe
r ye
ar
in 1
0,0
00
wo
me
n
E+P Placebo
Risk Benefit Neutral
Thromboembolic risk with oral Thromboembolic risk with oral vs. transdermal estradiol.vs. transdermal estradiol.
RXRX CasesCases
259259ControlsControls
603603adjustedadjusted
nonenone 146146 384384 11
Oral ETOral ET 4545 3939 4.2 (1.5-4.2 (1.5-11.6)11.6)
Patch ETPatch ET 6767 180180 0.9 (0.4-0.9 (0.4-2.1)2.1)
With progWith prog 1919 6363 0.7 (0.3-0.7 (0.3-1.9)1.9)
What is Primary Prevention?What is Primary Prevention?
Vascular Biologist's Definition
Cardiologist's Definition
Event
Adventitia
Media
Fatty Streak/Plaque
InternalElastic
Lamina
Necrotic Core
Plaque
FibrousCap
FibrousCap
Plaque
Primary PreventionPrimary Prevention
KEEPS – KEEPS – KKronos ronos EEarly arly EEstrogen strogen PPrevention revention SStudytudy720 women within 3 years of menopause720 women within 3 years of menopauseRandomized to premarin or estradiol Randomized to premarin or estradiol
patchespatchesCyclic progesterone (12 days per month).Cyclic progesterone (12 days per month).Primary OutcomePrimary Outcome – Carotid intimal –medial – Carotid intimal –medial
thickness (CIMT)thickness (CIMT)2° outcome2° outcome cognitive function and cognitive function and
inflammatory markers.inflammatory markers.
Other effects of EstrogensOther effects of Estrogens
On Skin – wrinkles and drooping?On Skin – wrinkles and drooping?Genitalia – vaginal thinning and drynessGenitalia – vaginal thinning and drynessSexual function- Sexual function-
DyspareuniaDyspareuniaDecreased libidoDecreased libido
MemoryMemoryGeneralized well beingGeneralized well beingDecreased headaches (some women)Decreased headaches (some women)
Aging of the SkinAging of the Skin
Dryness
Hair
Collagen Fibers
Skin Thickness
Glycosaminoglycans
Elasticity
Results in
Vascularity
Petersen MJ. Aging of the skin. In: Freinkel RK, Woodley DT, eds. The Biology of the Skin. New York, London: Parthenon; 2001:209-18.Young EM Jr, Newcomer VD. Anatomy of aging skin. In: Newcomer VD, Young EM Jr, eds. Geriatric Dermatology: Clinical Diagnosis and Practical Therapy. New York, Tokyo: Igaku-Shoin; 1989:9-15.
100
120
140
160
180
200
220
240
260
280
0 2 4 6 8 10 12 14 16
P < .001.Reprinted from Br J Obstet Gynaecol. Brincat M, et al. Long-term effects of the menopause and sex hormones on skin thickness. 1985;92:256-9. © 1985, with permission from Elsevier Science.
Collagen Content and Collagen Content and Menopausal AgeMenopausal Age
Th
igh
Co
llag
en C
on
ten
t (
g/m
m2 )
Years Since Menopause
ET/HT (n = 52)
Placebo (n = 77)
Vaginal BiopsiesVaginal Biopsies
Postmenopausal, atrophic Same patient, local ET (one month)
0
10
20
30
40
50
Per
cen
t
Dryness increased significantly in late perimenopause and postmenopause (P < .001).Dennerstein L, et al. Obstet Gynecol. 2000;96:351-8.
Pre-menopause
(n = 172)
EarlyPerimenopause
(n = 148)
LatePerimenopause
(n = 106)
Post-menopause
1 year(n = 72)
Post-menopause
2 years(n = 54)
Increase in Vaginal Dryness Increase in Vaginal Dryness With MenopauseWith Menopause
Post-menopause
3 years(n = 31)
3%
47%
21%25%
32%
4%
Effect of Menopausal Effect of Menopausal Transition on Parameters of Transition on Parameters of
Sexual FunctioningSexual FunctioningCross-sectional Data Reported From a Longitudinal, Population-based Cohort of Australian Women, 45–55 Years of Age
-0.17 -0.14
0.27
0.15
-0.20
-0.4
-0.2
0
0.2
0.4
SexualResponsivity
SexualFrequency
Libido VaginalDyspareunia
PartnerProblems
Mea
n C
han
ge
in S
PE
Q
(Sex
ual
) D
om
ain
s
n = 438; SPEQ = Shortened version of the Personal Experiences Questionnaire.*P < .05 for postmenopausal compared with perimenopausal women.Dennerstein L, et al. Fertil Steril. 2001;76:456-60.
* *
*
*
*
Must Weigh the Good vs. the Must Weigh the Good vs. the Bad of estrogen therapyBad of estrogen therapy
RisksRisks Long term Increase Long term Increase
in breast ca. in breast ca. HR=1.24 HR=1.24 (0.01%/woman/yr.)(0.01%/woman/yr.)
2-fold increase in 2-fold increase in venous thrombosis.venous thrombosis.
Endometrial cancerEndometrial cancer Early CAD events Early CAD events
HR=1.29.HR=1.29.
BenefitsBenefits Vasomotor Vasomotor
symptomssymptoms improved improved reduced 70%- 90%.reduced 70%- 90%.
Fractures decreased Fractures decreased rr=0.76rr=0.76
Vaginal symptoms Vaginal symptoms reduced.reduced.
Colon cancer reduced Colon cancer reduced rr=0.7rr=0.7
30% reduction in new 30% reduction in new diabetes (HERS + diabetes (HERS + WHI)WHI)
Summary Post Summary Post WHI WHI Estrogen Estrogen USEUSE
1)1) TreatmentTreatment is not the same as is not the same as preventionprevention. . 2)2) Treatment of menopausal symptomsTreatment of menopausal symptoms is is
still the main goal of still the main goal of estrogen therapyestrogen therapy..3)3) Estrogen/progestinEstrogen/progestin treatment treatment should be as should be as
shortshort as possible. No clinical trial data, as possible. No clinical trial data, <5years.<5years.
4)4) Generalized feelings of well-being may be Generalized feelings of well-being may be different and difficult to show.different and difficult to show.
5)5) Estrogen/progestin Estrogen/progestin should notshould not be used be used for for preventionprevention of of cardiaccardiac disease disease. .
Summary cont.Summary cont.
6)6) More research is needed to determine the More research is needed to determine the effect of estrogens when started at effect of estrogens when started at menopause.menopause.
7)7) More basic research is needed on estrogen’s More basic research is needed on estrogen’s mechanisms of action.mechanisms of action.
8)8) Menopause is a good time to review Menopause is a good time to review prevention of later chronic disorders (heart, prevention of later chronic disorders (heart, bone , cancers)bone , cancers)
9)9) Therapy needs to be individualized.Therapy needs to be individualized.
THE ENDTHE END
Estrogen TherapyEstrogen Therapy
EstrogensEstrogens Oral estrogens – conjugated equine Oral estrogens – conjugated equine
estrogensestrogens Oral estradiolOral estradiol
Systemic estradiol (transdermal patches or Systemic estradiol (transdermal patches or cream)cream)
In Woman who has a uterusIn Woman who has a uterusTo prevent endometrial hyperplasiaTo prevent endometrial hyperplasia: Add: Addo Medroxyprogesterone acetateMedroxyprogesterone acetateo ProgesteroneProgesteroneo NorethindroneNorethindroneGiven orally, transdermally or vaginallyGiven orally, transdermally or vaginally