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