Simon 2015

1

Update on Estrogen Therapy 2016

Is the WHI Still the Last Word On The Use of Estrogen

James A Simon MD CCD NCMP IF FACOGClinical Professor

Department of ObGynGeorge Washington University

Washington DC

Medical DirectorWomenrsquos Health amp Research Consultantsreg

Washington DCwwwJamesASimonMDcom

JamesASimonMDJames A Simon MD PC

Disclosures 2016Dr James A Simon has served (within the last year) or is currently serving asOwnerBoard of Directors James A Simon MD PCAdvisory BoardConsultant A consultant to or on the advisory boards of AbbVie Inc (North Chicago IL) AMAG Pharmaceuticals Inc (Waltham MA) Amgen Inc (Thousand Oaks CA) Apotex Inc (Toronto Canada) Ascend Therapeutics (Herndon VA) JDS Therapeutics LLC (Purchase NY) Merck amp Co Inc (Whitehouse Station NJ) Noven Pharmaceuticals Inc (New York NY) Novo Nordisk (Bagsvrerd Denmark) Nuelle Inc (Mountain View CA) Perrigo Company PLC (Dublin Ireland) Radius Health Inc (Waltham MA) Regeneron Pharmaceuticals Inc (Tarrytown NY) Roivant Sciences Inc (New York NY) Sanofi SA (Paris France) Sermonix Pharmaceuticals Inc (Columbus OH) Shionogi Inc (Florham Park NJ) Sprout Pharmaceuticals (Raleigh NC) Symbiotec Pharmalab (Indore India) TherapeuticsMD (Boca Raton FL)Speaker On the speakerrsquos bureaus of Amgen Inc (Thousand Oaks CA) Eisai Inc (Woodcliff Lake NJ) Merck (Whitehouse Station NJ) Noven Pharmaceuticals Inc (New York NY) Novo Nordisk (Bagsvrerd Denmark) Shionogi Inc (Florham Park NJ)GrantsResearch Receiving grantresearch support from AbbVie Inc (North Chicago IL) Actavis PLC (Dublin Ireland) Agile Therapeutics (Princeton NJ) Bayer Healthcare LLC (Tarrytown NY) New England Research Institute Inc (Watertown MA) Novo Nordisk (Bagsvrerd Denmark) Palatin Technologies (Cranbury NJ) Symbio Research Inc (Port Jefferson NY) TherapeuticsMD (Boca Raton FL)Patent and Trademark Holder US Patent 4816257 March 28 1989 Method for Producing an In Vivo Environment Suitable for Human Embryo Transplant US Trademark Reg No 3446895 Registered June 10 2008 ldquoYou talkhellipIrsquoll Listen Wersquoll Plan Togetherrdquo US Trademark Reg No 3676269 Registered September 1 2009 US Trademark Reg No 3760080 Registered March 16 2010 ldquoWomenrsquos Health amp Research Consultants amp Designrdquo US Trademark Serial No86-714153 ldquoDR SIMON SAYSrdquo Registered February 2 2016Stock Shareholder andor other Financial Support Dr Simon is a stockholder (direct purchase) in Sermonix Pharmaceuticals (Columbus OH)Dr Simon served as chief medical officer (CMO) of Sprout Pharmaceuticals until April 2013

Thank You

Dr Howard Hodis

Dr Philip Sarrel

NIH

Learning Objectives

Upon completion of this lecture participants will be able to

Describe the current statusoutcomes of the WHI KEEPS ELITE and other current hormone therapy (HT) and estrogen therapy (ET) trials and have a contextual understanding of their clinical implications to date

Understand the tenets of the gap hypothesis and how it applies differentially to cardiovascular disease vs breast cancer

Have a working knowledge of how route of administration could impact the overall riskbenefit ratio for postmenopausal systemic HT or ET

Appreciate the alternatives to standard progestogens for endometrial protection

Zombie Idea

ldquoAn idea that should have been killed by evidence but refuses to dierdquo

Paul Krugman Nobel Prize in Economics 2008 NYT March 30 2014

Slide by Voelker EE and Sarrel PM

NB ldquoZombiesrdquo tap into deep-rooted irrational human fears

WHI received enormous media coverage ndash more than 400 newspaper stories and 2500 television-radio storieshellip

Annals of Internal Medicine V0l 140(3) pp226

The Truth About Hormones ndash

Hormone Replacement Therapy is

Riskier Than Advertised Whatrsquos a

woman to do

July 22 2002

The End of the Age of Estrogen

July 22 2002

Hormone Therapy The Danger Assessed

May 27 2003

Another Study Slams Hormone Pills The Replacement Regimen Doesnrsquot Help Improve

Womenrsquos Memory or Mood Researchers Said March 18 2003

Hormone Hazards

July 29 2002

Study Dismissed HRT As Clinically Useless

March 18 2003

A New Blow to Hormone Therapy

June 24 2003

Bad to Worse Major Findings by a Government Study

of Hormone Therapy for Women August 7

2003

Hormone Therapyrsquos Use Knocked Again

August 7 2003

And what about the embargo

Simon 2015

2

Vasomotor Symptoms and Related Psychosocial

Impairment During the Menopausal Transition

bull Hot flushes

bull Night sweats

bull Sleep disturbances

ndash Insomnia

ndash Sleep apnea

bull Mood swings

ndash Irritability

ndash Sadness

ndash Tension

bull Cognitive deficits

ndash Poor concentration

ndash Verbal memory problems

bull Social Impairment

ndash Disruption of family relationships

ndash Social Isolation

bull Work Related Difficulties

ndash Reduced Productivity

bull Other Quality-of-life Impairment

ndash Embarrassment

ndash Anxiety

ndash Fatigue

Utian WH Psychosocial and socioeconomic burden of vasomotor symptoms in menopause a comprehensive review

Health Qual Life Outcomes 2005 Aug 5347

Simon JA and Reape KZ Understanding the menopausal experiences of professional women Menopause 2009 16 (1) 73-76

Decline in the Use of Postmenopausal HT In the US 1999-2010

HT Use in Women gt 40 years () 1999-2000 2009-2010

Any formulation 224 47

Estrogen only 133 27

Estrogen + Progestogen 83 17

plt 001 for all comparisons 1999-2000 vs 2009-2010

Source Sprague BL et al Obstet Gynecol 2012120595-603

Causes of Death Among US Women

Source Ten Leading Causes of Death 2011-2012 (National Vital Statistics SystemNCHSCDC)

The Womanrsquos Health Initiative

(July 2002 WHI Press Conference RE E+P)

WHI-E+P Relative and Absolute RiskWomen 50 to 79 (mean 635) Years of Age at Baseline

Breast cancer

Strokes

VTE

Colorectal cancer

Hip fractures

Total fractures

New onset diabetes

Overall

Hazard

Ratio

Absolute Risk

per 10000

WomenYearHealth Event

126

131

211

056

067

076

079

8

7

18

7

5

47

15

Absolute Benefit

per 10000

WomenYear

Nominal

95

100ndash159

102ndash168

158ndash282

038ndash081

047ndash096

069ndash085

067ndash093

Adjusted

95

083ndash192

093ndash184

126ndash355

033ndash094

041ndash110

063ndash092

Confidence Interval

Cauley JA et al JAMA 20032901729-38 Chlebowski RT et al N Engl J Med 2004350991-1004 Chlebowski RT et al JAMA

20032893243-53 Manson JE et al N Engl J Med 2003349523-534 Wassertheil-Smoller S et al JAMA 2003 2892673-84

Margolis KL et al Diabetologia 2004471176-87 Writing Group for the Womens Health Initiative Investigators JAMA

2002288321-33

CHD 129 102ndash163 085ndash197 7

CHD-Revised 124 100ndash154 097ndash160 6

Breast cancer 124 101ndash154 097ndash159 8

3070ndash255087ndash206134PE

56059ndash083063ndash079070Total fractures

6033ndash111041ndash091061Hip fractures

1063ndash186075ndash155108Colorectal cancer

7086ndash208099ndash179133VTE

12097ndash199110ndash177139Strokes

7057ndash106059ndash101077Breast cancer

5072ndash115075ndash112091CHD

Absolute Benefit

per 10000

WomenYear

Absolute Risk

per 10000

WomenYear

95

Adjusted

95

NominalOverall

HREvent

Confidence Intervals

Womens Health Initiative Steering Committee JAMA 20042911701-1712

WHI-E Relative and Absolute RiskWomen 50 to 79 (mean 64) Years of Age at Baseline

14077ndash101New onset diabetes 088

Simon 2015

3

Rates for Everyday Life Events and Adverse Drug Reactions

Event (United States)

Rate

(per 100000

population) Same as Translates to

Traffic Death Rate (2009)1 110 0011 11 in 10000

Maternal death during pregnancy

and childbirth (2010)2 21 0021 21 in 10000

Identify Theft (2010)3 812 00812 812 in 10000

Total Violent Crime (2009)4 1690 169 169 in 10000

1 httpwwwcensusgovcompendiastatab2012tables12s1103 pdf 2 httpdataworldbankorgindicatorSHSTAMMRT

3 httpwwwcensusgovcompendiastatab2012tables12s0337pdf 4 httpbjsojpusdojgovcontentglancetablesviortrdtabcfm 5 Guidelines for preparing

core clinical safety information on drugs 2nd Ed Report of CIOMS Working Groups III and IVCIOMS Geneva 1999

Frequency of Adverse Drug Reactions (CIOMS)5 Same as Translates to

Very common ge110 ge 10 More than 1000 in 10000

Common (frequent) ge1100 and lt 110 ge 1 to lt 10 Between 100 and 999 in 10000

Uncommon (infrequent) ge11000 and lt 1100 ge 01 to lt 1 Between 10 and 99 in 10000

Rare ge110000 and lt 11000 ge001 to lt 01 Between 1 and 9 in 10000

Very rare lt110000 lt 001 1 or less in 10000

CIOMS= Council for International Organizations of Medical Sciences

WHI E+P SubstudyRisk by Age

-1-04

1

-08-02

0

1914

0208

12

-05 -03

17

03

-07

-2

-1

-5

-3

-1

1

3

5

CHD Invasive breast cancer

Stroke VTE

Colorectal cancer Hip fracture

WHI E-Alone SubstudyRisk by Age

Absolute (attributable) risk per 1000 women

Age 50-59 Age 60-69 Age 70-79

Placebo (baseline risk)

Womens Health Initiative Steering Committee JAMA 20042911701-1712 Hsia J et al Arch Intern Med 2006166357-365

Nu

mb

er o

f E

ven

ts

Final centrally adjudicated data as reported in The Womenrsquos Health Initiative Steering Committee Effects of conjugated equine estrogen in postmenopausal women with hysterectomy The Womenrsquos Health Initiative Randomized Controlled Trial JAMA 20042911701-1712

daggerSignificance by hazard ratio and 95 confidence interval

dagger

dagger

dagger

WHI Post-Intervention ReportsET+P 20101 and ET 20112

1 Chlebowski et al JAMA 2010304 (15)1684-1692

2 LaCroix AZ et al JAMA 2011305 (13)1305-1314

1 Rossouw JE et al JAMA 2002288(3)321-333 2 Anderson GL et al JAMA 2004291(14)1701-1712 3 LaCroix AZ et al JAMA 2011305 (13)1305-1314

4 Chlebowski RT et al JAMA 2010304 (15)1684-1692

Results of the WHI After More Than a

Decade of Follow-up

Enrolled More Than 27000 Menopausal Women Aged 50 to 79 Years12

Women who had a hysterectomy

Placebo (n= 5429)CEE (n=5310)

CEE (vs placebo)

No significant change in risk of

coronary heart disease (CHD) Persistence of decreased risk of

breast cancer3

CEE + MPA (vs placebo)

Increased risk of breast cancer and breast

cancer mortality4

Major outcomes after 110 years(mean intervention 56 years)4

Women with an intact uterus

Major outcomes after 107 years(mean intervention 71 years)3

Placebo (n= 8102)CEE + MPA (n=8506)

17

HRT and CV Risk by Age WHI Second Arm (Estrogen Alone after Hysterectomy)

Age

50-59 60-69 70-79

59 10 106

54 105 126

73 104 81

80 73 81

CHD

MI

Mortality

Breast Ca

LaCroix AZ et al JAMA 2011305(13)1305-14

Simon 2015

4

50 years = mean age7 months = mean time from menopause252 kgm

2= mean BMI

Year

Pro

po

rtio

n o

f Su

bje

cts

Wit

ho

ut

CV

D o

r D

eat

h

p = 0020

p = 0015

Schierbeck LL et al BMJ 20123456e6409 DOPS=Danish Osteoporosis Prevention Study

No at risk

HRT 502 502 498 496 483 487 484 477 155

Control 504 502 497 492 484 475 466 455 90

DOPS CVD Outcomes

10 y of RTC HT or ET reduced mortality CHF or MI

No increase in CA VTE or Stroke

ET and HT vs Placebo and Breast Cancer in The WHI

Anderson G Lancet Oncology Mar 2012 (Slide Courtesy of Dr Lila Nachtigall)

E

E+P

Manson JE et al JAMA 20133101353-1368

-30

-20

-10

0

10

20

30

Deep VeinThrombosis

PulmonaryEmbolus

BreastCancer

Stroke All-CauseMortality

All CancerDeaths

ColorectalCancer

All CancerTypes

All Fractures Diabetes

100

60 50 60

minus100 minus40 minus10 minus10

minus250

minus110

Ab

solu

te R

isk

ndashN

um

ber

of

Even

ts p

er 1

000

0 W

om

en p

er Y

ear

Ben

efit

sR

isks

-30

-20

-10

0

10

20

30

50 30

minus10 minus50

minus110

minus40 minus30 minus80

minus160

minus260

Deep VeinThrombosis

PulmonaryEmbolus

BreastCancer

All-CauseMortality

All CancerDeaths

ColorectalCancer

All CancerTypes

All Fractures DiabetesStroke

Ab

solu

te R

isk

ndashN

um

ber

of

Even

ts p

er 1

000

0 W

om

en p

er Y

ear

Ben

efit

sR

isks

CE Trial

CE +MPA Trial

Absolute Benefits and Risks from WHI ndash Initiation of HT in Women 50-59 Years of Age Number of Events

per 10000 Women per YearManson JE

Kaunitz AM

Menopause

Management

mdash Getting

Clinical Care

Back on Track

N Engl J Med

2016 374(9)

803-806

Kronos Early Estrogen Prevention Study (KEEPS) Design

bull N=727 menopausal women aged 42-59 (mean age 527 within 3 years of LMP)bull Trial Duration 48 monthsbull Design Multicenter double blind placebo controlled RCTbull Treatment Arms

bull Oral conjugated equine estrogens (o-CEE) given as Premarinreg 045 mgd (lower dose than WHI)

bull Transdermal estradiol (t-E2) given by Climarareg patch 005 mgdbull Placebo

(active arms received cyclical micronized progesterone [Prometriumreg] 200 mgd x 12 dmo placebo arm received placebo Prometriumreg)

Wharton W Gleason CE Miller VM Asthana S Rationale and Design of the Kronos Early Estrogen Prevention Study (KEEPS) and the KEEPS Cognitive and Affective Sub-Study (KEEPS Cog) Brain Res 2013 June 13 1514 12ndash17

KEEPS Directions of Changes in CHD Risk Factors

Factor O-CEE T-E2

Systolic BP Neutral Neutral

Diastolic BP Neutral Neutral

LDL Cholesterol Favorable Neutral

Triglycerides Adverse Neutral

HDL Cholesterol Favorable Neutral

Fasting Glucose Neutral Favorable

HOMA-IR Neutral Favorable

CHD Coronary Heart Disease HOMA-IR homeostasis model assessment-estimated insulin resistance

o-CEE is Premarin 045mgdt-E2 is Climara 005 mcgd

Simon 2015

3

Rates for Everyday Life Events and Adverse Drug Reactions

Event (United States)

Rate

(per 100000

population) Same as Translates to

Traffic Death Rate (2009)1 110 0011 11 in 10000

Maternal death during pregnancy

and childbirth (2010)2 21 0021 21 in 10000

Identify Theft (2010)3 812 00812 812 in 10000

Total Violent Crime (2009)4 1690 169 169 in 10000

1 httpwwwcensusgovcompendiastatab2012tables12s1103 pdf 2 httpdataworldbankorgindicatorSHSTAMMRT

3 httpwwwcensusgovcompendiastatab2012tables12s0337pdf 4 httpbjsojpusdojgovcontentglancetablesviortrdtabcfm 5 Guidelines for preparing

core clinical safety information on drugs 2nd Ed Report of CIOMS Working Groups III and IVCIOMS Geneva 1999

Frequency of Adverse Drug Reactions (CIOMS)5 Same as Translates to

Very common ge110 ge 10 More than 1000 in 10000

Common (frequent) ge1100 and lt 110 ge 1 to lt 10 Between 100 and 999 in 10000

Uncommon (infrequent) ge11000 and lt 1100 ge 01 to lt 1 Between 10 and 99 in 10000

Rare ge110000 and lt 11000 ge001 to lt 01 Between 1 and 9 in 10000

Very rare lt110000 lt 001 1 or less in 10000

CIOMS= Council for International Organizations of Medical Sciences

WHI E+P SubstudyRisk by Age

-1-04

1

-08-02

0

1914

0208

12

-05 -03

17

03

-07

-2

-1

-5

-3

-1

1

3

5

CHD Invasive breast cancer

Stroke VTE

Colorectal cancer Hip fracture

WHI E-Alone SubstudyRisk by Age

Absolute (attributable) risk per 1000 women

Age 50-59 Age 60-69 Age 70-79

Placebo (baseline risk)

Womens Health Initiative Steering Committee JAMA 20042911701-1712 Hsia J et al Arch Intern Med 2006166357-365

Nu

mb

er o

f E

ven

ts

Final centrally adjudicated data as reported in The Womenrsquos Health Initiative Steering Committee Effects of conjugated equine estrogen in postmenopausal women with hysterectomy The Womenrsquos Health Initiative Randomized Controlled Trial JAMA 20042911701-1712

daggerSignificance by hazard ratio and 95 confidence interval

dagger

dagger

dagger

WHI Post-Intervention ReportsET+P 20101 and ET 20112

1 Chlebowski et al JAMA 2010304 (15)1684-1692

2 LaCroix AZ et al JAMA 2011305 (13)1305-1314

1 Rossouw JE et al JAMA 2002288(3)321-333 2 Anderson GL et al JAMA 2004291(14)1701-1712 3 LaCroix AZ et al JAMA 2011305 (13)1305-1314

4 Chlebowski RT et al JAMA 2010304 (15)1684-1692

Results of the WHI After More Than a

Decade of Follow-up

Enrolled More Than 27000 Menopausal Women Aged 50 to 79 Years12

Women who had a hysterectomy

Placebo (n= 5429)CEE (n=5310)

CEE (vs placebo)

No significant change in risk of

coronary heart disease (CHD) Persistence of decreased risk of

breast cancer3

CEE + MPA (vs placebo)

Increased risk of breast cancer and breast

cancer mortality4

Major outcomes after 110 years(mean intervention 56 years)4

Women with an intact uterus

Major outcomes after 107 years(mean intervention 71 years)3

Placebo (n= 8102)CEE + MPA (n=8506)

17

HRT and CV Risk by Age WHI Second Arm (Estrogen Alone after Hysterectomy)

Age

50-59 60-69 70-79

59 10 106

54 105 126

73 104 81

80 73 81

CHD

MI

Mortality

Breast Ca

LaCroix AZ et al JAMA 2011305(13)1305-14

Simon 2015

4

50 years = mean age7 months = mean time from menopause252 kgm

2= mean BMI

Year

Pro

po

rtio

n o

f Su

bje

cts

Wit

ho

ut

CV

D o

r D

eat

h

p = 0020

p = 0015

Schierbeck LL et al BMJ 20123456e6409 DOPS=Danish Osteoporosis Prevention Study

No at risk

HRT 502 502 498 496 483 487 484 477 155

Control 504 502 497 492 484 475 466 455 90

DOPS CVD Outcomes

10 y of RTC HT or ET reduced mortality CHF or MI

No increase in CA VTE or Stroke

ET and HT vs Placebo and Breast Cancer in The WHI

Anderson G Lancet Oncology Mar 2012 (Slide Courtesy of Dr Lila Nachtigall)

E

E+P

Manson JE et al JAMA 20133101353-1368

-30

-20

-10

0

10

20

30

Deep VeinThrombosis

PulmonaryEmbolus

BreastCancer

Stroke All-CauseMortality

All CancerDeaths

ColorectalCancer

All CancerTypes

All Fractures Diabetes

100

60 50 60

minus100 minus40 minus10 minus10

minus250

minus110

Ab

solu

te R

isk

ndashN

um

ber

of

Even

ts p

er 1

000

0 W

om

en p

er Y

ear

Ben

efit

sR

isks

-30

-20

-10

0

10

20

30

50 30

minus10 minus50

minus110

minus40 minus30 minus80

minus160

minus260

Deep VeinThrombosis

PulmonaryEmbolus

BreastCancer

All-CauseMortality

All CancerDeaths

ColorectalCancer

All CancerTypes

All Fractures DiabetesStroke

Ab

solu

te R

isk

ndashN

um

ber

of

Even

ts p

er 1

000

0 W

om

en p

er Y

ear

Ben

efit

sR

isks

CE Trial

CE +MPA Trial

Absolute Benefits and Risks from WHI ndash Initiation of HT in Women 50-59 Years of Age Number of Events

per 10000 Women per YearManson JE

Kaunitz AM

Menopause

Management

mdash Getting

Clinical Care

Back on Track

N Engl J Med

2016 374(9)

803-806

Kronos Early Estrogen Prevention Study (KEEPS) Design

bull N=727 menopausal women aged 42-59 (mean age 527 within 3 years of LMP)bull Trial Duration 48 monthsbull Design Multicenter double blind placebo controlled RCTbull Treatment Arms

bull Oral conjugated equine estrogens (o-CEE) given as Premarinreg 045 mgd (lower dose than WHI)

bull Transdermal estradiol (t-E2) given by Climarareg patch 005 mgdbull Placebo

(active arms received cyclical micronized progesterone [Prometriumreg] 200 mgd x 12 dmo placebo arm received placebo Prometriumreg)

Wharton W Gleason CE Miller VM Asthana S Rationale and Design of the Kronos Early Estrogen Prevention Study (KEEPS) and the KEEPS Cognitive and Affective Sub-Study (KEEPS Cog) Brain Res 2013 June 13 1514 12ndash17

KEEPS Directions of Changes in CHD Risk Factors

Factor O-CEE T-E2

Systolic BP Neutral Neutral

Diastolic BP Neutral Neutral

LDL Cholesterol Favorable Neutral

Triglycerides Adverse Neutral

HDL Cholesterol Favorable Neutral

Fasting Glucose Neutral Favorable

HOMA-IR Neutral Favorable

CHD Coronary Heart Disease HOMA-IR homeostasis model assessment-estimated insulin resistance

o-CEE is Premarin 045mgdt-E2 is Climara 005 mcgd

Simon 2015

4

50 years = mean age7 months = mean time from menopause252 kgm

2= mean BMI

Year

Pro

po

rtio

n o

f Su

bje

cts

Wit

ho

ut

CV

D o

r D

eat

h

p = 0020

p = 0015

Schierbeck LL et al BMJ 20123456e6409 DOPS=Danish Osteoporosis Prevention Study

No at risk

HRT 502 502 498 496 483 487 484 477 155

Control 504 502 497 492 484 475 466 455 90

DOPS CVD Outcomes

10 y of RTC HT or ET reduced mortality CHF or MI

No increase in CA VTE or Stroke

ET and HT vs Placebo and Breast Cancer in The WHI

Anderson G Lancet Oncology Mar 2012 (Slide Courtesy of Dr Lila Nachtigall)

E

E+P

Manson JE et al JAMA 20133101353-1368

-30

-20

-10

0

10

20

30

Deep VeinThrombosis

PulmonaryEmbolus

BreastCancer

Stroke All-CauseMortality

All CancerDeaths

ColorectalCancer

All CancerTypes

All Fractures Diabetes

100

60 50 60

minus100 minus40 minus10 minus10

minus250

minus110

Ab

solu

te R

isk

ndashN

um

ber

of

Even

ts p

er 1

000

0 W

om

en p

er Y

ear

Ben

efit

sR

isks

-30

-20

-10

0

10

20

30

50 30

minus10 minus50

minus110

minus40 minus30 minus80

minus160

minus260

Deep VeinThrombosis

PulmonaryEmbolus

BreastCancer

All-CauseMortality

All CancerDeaths

ColorectalCancer

All CancerTypes

All Fractures DiabetesStroke

Ab

solu

te R

isk

ndashN

um

ber

of

Even

ts p

er 1

000

0 W

om

en p

er Y

ear

Ben

efit

sR

isks

CE Trial

CE +MPA Trial

Absolute Benefits and Risks from WHI ndash Initiation of HT in Women 50-59 Years of Age Number of Events

per 10000 Women per YearManson JE

Kaunitz AM

Menopause

Management

mdash Getting

Clinical Care

Back on Track

N Engl J Med

2016 374(9)

803-806

Kronos Early Estrogen Prevention Study (KEEPS) Design

bull N=727 menopausal women aged 42-59 (mean age 527 within 3 years of LMP)bull Trial Duration 48 monthsbull Design Multicenter double blind placebo controlled RCTbull Treatment Arms

bull Oral conjugated equine estrogens (o-CEE) given as Premarinreg 045 mgd (lower dose than WHI)

bull Transdermal estradiol (t-E2) given by Climarareg patch 005 mgdbull Placebo

(active arms received cyclical micronized progesterone [Prometriumreg] 200 mgd x 12 dmo placebo arm received placebo Prometriumreg)

Wharton W Gleason CE Miller VM Asthana S Rationale and Design of the Kronos Early Estrogen Prevention Study (KEEPS) and the KEEPS Cognitive and Affective Sub-Study (KEEPS Cog) Brain Res 2013 June 13 1514 12ndash17

KEEPS Directions of Changes in CHD Risk Factors

Factor O-CEE T-E2

Systolic BP Neutral Neutral

Diastolic BP Neutral Neutral

LDL Cholesterol Favorable Neutral

Triglycerides Adverse Neutral

HDL Cholesterol Favorable Neutral

Fasting Glucose Neutral Favorable

HOMA-IR Neutral Favorable

CHD Coronary Heart Disease HOMA-IR homeostasis model assessment-estimated insulin resistance

o-CEE is Premarin 045mgdt-E2 is Climara 005 mcgd

Simon 2015

5

Harman SM Black DM Naftolin F et al Arterial imaging outcomes and cardiovascular risk factors

in recently menopausal women a randomized trial Ann Intern Med 2014 Aug 19161(4)249-60

KEEPS

KEEPS Overall Summary amp Conclusions+

bull Similarities Both o-CEE and t-E2 had ndash neutral favorable effects on CVD biomarkers (differences related

to first-pass liver metabolism)ndash neutral effects on CIMT and CAC (ns trend for CAC benefit)ndash neutral effects on cognition favorable effects on VMS

bull Differences ndash o-CEE improved moodndash t-E2 improved HOMA-IR and some advantages on sexual function

bull Conclusionsndash KEEPS highlights the need for individualized decision making about

HT by treatment priorities and risk factor statusndash Additional research on HT in newly menopausal women (ie

formulationsdosesroutes of delivery) is needed+ Presented by JoAnn E Manson MD DrPH NCMP at NAMS Annual Meeting October 11 2013

Early vs Late Intervention Trial with

Estradiol (ELITE)

The ldquotiming hypothesisrdquo posits that there is a differential effect on atherosclerosis and clinical events according to when postmenopausal HRT is initiated in relation to menopause

Timing Hypothesis

Hodis HN et al J Am Geriatr Soc 2013611005-1010

Hodis HN et al J Am Geriatr Soc 2013611011-1018 Slide Courtesy of Dr Cynthia Stuenkel

Simon 2015

6

Pathogenic Sequence of Vascular AgingNo HRT Adventitia

Media

Fatty StreakPlaque

InternalElasticLamina

Necrotic Core

Plaque

FibrousCap

FibrousCap

Plaque Necrotic Core

Plaque

FibrousCap

MMP-9

EPAT = HRT Early amp Continued

WELL-HART = HRT Late

HRT

Age 35-45 years Age 45-55 years Age 55-65 years Age gt65 years

HRT

Mural Thrombus

Hodis HN et al N Eng J Med 2003349535ndash545

ELITE - Design

Study design Single-center randomized double-blinded placebo-controlled trial with a 2 x 2 factorial design

Subjects 643 healthy recently postmenopausal (lt6 years) and remotely postmenopausal women (gt10 years) without preexisting CVD and diabetes mellitus

Intervention Oral micronized 17β-estradiol 1 mgd (+ 45 mg vaginal micronized progesterone gel x 10 days every month in women with a uterus) Or Matching Placebos

Follow-up Every month for the first 6 months and then every 2 months for 5-6 years

Funding NIH ndash National Institute on Aging (R01AG-024154)

ELITE TRIAL RESULTS

Hodis HN Mack WJ Henderson VW et al Vascular Effects of Early versus Late

Postmenopausal Treatment with Estradiol N Engl J Med 20163741221-31

Hodis HN Mack WJ Henderson VW et al Vascular Effects of Early versus Late

Postmenopausal Treatment with Estradiol N Engl J Med 20163741221-31

All Ages

gt10 years since menopause

gt60 years old

lt10 years since menopause

lt60 years old

025 050 10 15 20

Relative Risk (95 CI)

099 (088-111)

068 (048-096)

103 (091-116)

CHD Events Associated with HRT inYounger and Older Women

Meta-analysis of 23 Randomized Controlled Trials (191340 patient-years)

Salpeter S et al J Gen Intern Med 200621363-366

Mortality

Simon 2015

7

All-Cause Mortality Associated with HRT in Younger and Older Women Meta-analysis of 30 Randomized

Controlled Trials (119118 patient-years)

025 050 10 15 20

Relative Risk (95 CI)

098 (087-118)

061 (039-095)

103 (090-118)

Salpeter SR et al J Gen Intern Med 200419791-804

All Ages

gt60 years old

Mean age = 66 years

lt60 years old

Mean age = 54 years

gt10 years since menopause

gt60 years old

lt10 years since menopause

lt60 years old

025 050 10 15

Relative Risk (95 CI)

070 (052-095)

106 (095-118)

Cochrane Meta-analysisAll-Cause Mortality from Randomized Controlled Trials of HRT in Younger and Older Postmenopausal Women

Boardman HMP et al Cochrane Database of Systemic Reviews 2015 Issue 3CD002229 DOI 10100214651858CD002229pub4

Bayesian Meta-Analysis of HRT and All-Cause Mortality in Younger (mean age 545 years) Postmenopausal Women

19 randomized controlled trials- 16283 women- 83043 patient-years- mean 51 years (1-68 years)

8 prospective observational studies- 212717 women- 2935495 patient-years- 138 years (6-22 years)

Randomized controlled trials andobservational studies combined

025 050 10 15 20

Relative Risk (95 CI)

073 (052-096)

072 (062-082)

078 (069-090)

Salpeter SR et al Am J Med 20091221016-1022

Sex-Specificity of Primary Prevention Therapies

Primary vs Secondary Prevention of CHD with Lipid-Lowering Therapy in Women

025 050 10 15 20

Relative Risk (95 CI)

CHD events

Non-fatal MI

CHD mortality

Total mortality

080 (071-091)

074 (055-100)

Secondary Prevention8 RCTs

8272 Women

073 (059-090)

100 (077-129)

025 050 10 15 20

Relative Risk (95 CI)

089 (069-109)

107 (047-204)

061 (022-168)

095 (062-146)

Primary Prevention6 RCTs

11435 Women

Walsh JME et al JAMA 20042912243-2252

Meta-Analysis of Primary Prevention of

CHD with Statin Therapy in Women vs Men

025 050 10 15 20

Relative Risk (95 CI)

072 (061-086)N=26921

095 (086-106)N=26921

Men

025 050 10 15 20

Relative Risk (95 CI)

CHD events

Total mortality

079 (056-113)N=20817

091 (076-108)N=20817

Women

Brugts JJ et al BMJ 2009338b2376

Simon 2015

8

Meta-Analysis of Primary Prevention of

CHD with Statin Therapy in Women vs Men

025 050 10 15 20

Relative Risk (95 CI)

055 (041-075)N=28346

093 (083-104)N=20426

Men

025 050 10 15 20

Relative Risk (95 CI)

CHD events

Total mortality

095 (078-116)N=13346

096 (081-113)N=11849

Women

Petretta M et al Int J Cardiol 201013825-31

Breast Cancer in Randomized Controlled Trials of Hormone and Statin Therapy

TherapyPlacebo Study

-21005 (053)5 (055)

8097-159124199 (042)150 (033)

CEE+MPA

WHI-EP

12077-21913032 (057)25 (045)HERS

15078-34916518 (038)11 (023)

STATIN

PROSPER

95 CI

No of Patients (Annualized )

No Additional Breast Cancer Cases per 10000 Women per

Year of TherapyRelative Risk

15062-33614413 (050)9 (035)AFCAPS

5046-4521447 (017)5 (011)4S-10 y fu

77248-5980121712 (082)1 (007)CARE

0042-24210010 (022)10 (022)LIPID

-2058-14809334 (028)37 (030)ALLHAT-LLT

-8065-104082129 (034)161 (042)

CEE alone

WHI-E

030-350

17B-E2 alone

WEST

-10049-11307538 (030)51 (040)HPS

025 050 10 15 20

Relative Risk (95 CI)

MI

Stroke

Total mortality

101 (084-121)N=51342

094 (074-119)N=51342

Women

083 (070-097)N=51342

025 050 10 15 20

Relative Risk (95 CI)

068 (054-086)N=44114

093 (085-103)N=44114

Men

113 (096-133)N=44114

Meta-Analysis of Primary Prevention of CVD with Aspirin in Women vs Men

Berger JS et al JAMA 2006295306-313

Are Transdermal Preparations Safer

CHDbull In a Danish national registry significantly lower risk of MI was found with

the transdermal route than with oral unopposed estrogen (P=004)2 STROKEbull In a nested case-control study from the UK General Practice Research

database (n=15710) the risk of stroke was not increased with low-dose transdermal estrogen (50 mcg) but did increase with higher transdermal doses and oral therapies3

VTEbull In a French systematic review and meta-analysis the risk of first-time

VTE was increased in oral estrogen users but not in transdermal estrogen users (OR 25 [19ndash34] for oral 12 [09ndash17] for transdermal)1

1 Canonico et al BMJ 2008 336 (7655) 1227-1231 2 Loslashkkegaard E Andreasen AH Jacobsen RK et al Eur Heart J 2008 29 2660-83 Renoux C et al BMJ 2010340c2519

Adjusted Incidence Rate Ratio of CVD Events

Transdermal ET vs Oral ET (sensitivity analysis)Increased Risk of Venous Thrombosis with

Conjugated Equine Estrogens (CEE) vs Estradiol

Smith NL Blondon M Wiggins KL et al Lower Risk of Cardiovascular Events in Postmenopausal Women Taking Oral Estradiol Compared With Oral Conjugated Equine Estrogens JAMA Intern Med 2014174(1)25-34

Simon 2015

9

Transdermal estrogen and

change in body weight or BMI

bull ldquoOne crossover study noted greater fat gain with

oral vs transdermal estrogen results that are

supported by clinical datardquo

Santen RJ Postmenopausal Hormone Therapy An Endocrine Society Scientific Statement JCEM201095S1S1-S66

Breast Cancer

The HeadlinesThe Womenrsquos Health Initiative Results (E + P)

41 Increase in Strokes 29 Increase in Heart Attacks 100 Increase in Venous Thromboembolism 22 Increase in Total CV Disease

26 Increase in Breast Cancer (331000 increased to 411000 for each year)

37 Decrease in Colorectal Cancer 33 Decrease in Hip Fracture 24 Decrease in Total Fractures No Difference in All Cause Mortality

None 12304 114 vs 102 106 081-138

lt5 yrs 3005 32 vs 15 213 115-394

5-10 yrs 783 11 vs 2 461 101-2102

gt10 yrs 515 9 vs 5 181 060-543

YRS N HT vs PBO HR 95 CI

WHI Breast Cancer

by Years of Prior Use (E + P) [2002]

Writing Group for Womenrsquos Health Initiative Investigators JAMA 2002 288

0

001

002

003

004

0 1 2 3 4 5 6 7

WHI E+P Trial No Effect of E+P on Risk of In Situ Breast Cancer

Cu

mu

lati

ve

Pro

port

ion

Time (years)

Chlebowski RT et al JAMA 2003289(24)3243-3253

Placebo

EP

HR = 118

95 CI = 077ndash182

Stefanick ML et al JAMA 2006295(14)1647-1657Permission to reprint requested from the American Medical Association

Cumulative Hazard for Total Invasive and In Situ Breast CancerEstrogen-Only

Simon 2015

10

The Gap or Timing Hypothesis (earlier ldquobetterrdquo later ldquoworserdquo)

This Gap Hypothesis also seems to apply to

Mood1

Dementia2

Ischemic Stroke3

Mild cognitive impairment4

Parkinsonrsquos Disease5

1Soares CN Maki PM Menopausal transition mood and cognition an integrated view to close the gaps Menopause 2010 17 (4) 812-8142Rocca WA Grossardt BR Shuster LT Stewart EA Hysterectomy Oophorectomy Estrogen and the Risk of Dementia Neurodegener Dis 2012 Jan 21 [Epub ahead of print]3Rocca WA Grossardt BR Miller VM Shuster LT Brown RD Jr Premature menopause or early menopause and risk of ischemic stroke Menopause 2012 Mar19(3)272-74Rocca WA Grossardt BR Shuster LT Oophorectomy menopause estrogen treatment and cognitive aging clinical evidence for a window of opportunity Brain Res

2011 Mar 161379188-98 Epub 2010 Oct 18 Review5Rocca WA Bower JH Maraganore DM Ahlskog JE Grossardt BR de Andrade M Melton LJ 3rd Increased risk of parkinsonism in women who underwent oophorectomy

before menopause Neurology 2008 Jan 1570(3)200-9 Epub 2007 Aug 29

Outcomes WHI-E RUTH

n= 10739 n=10101

mean age 636 years 675 years

mean follow-up 68 years 56 years

No cases10000 womenyear of treatment

CHD -5 -7

Stroke 12 (8) 9

VTE 7 11

PE 4 4

DVT 6 6

Breast cancer -8 -8

Bone fracture -56 -15

Hsia et al Arch Intern Med 2006166357-365

Writing Group for the Womens Health Initiative Investigators JAMA 20042911701-1712

Curb JD et al Arch Intern Med 2006166772-780

Stefanick ML et al JAMA 20062951647-1657

RUTH New Engl J Med 2006355125-137

WHI-E in Perspective (Not Head-To-Head)

Does the type of

progestogen matter

Is There a Difference Among Progestins

bull Comparative data is insufficient

bull Current research is ongoing in light of WHI findings

that suggested possible harm from progesterone (EPT

compared with ET)

bull PEPI a large RCT suggested micronized

progesterone has less negative impact on lipids

bull Small trials suggest VTE with micronized

progesterone

bull Caveat formulated in a peanut oil suspension so

ask about peanut allergies

Canonico et al Circulation 2007115(7)840-845

Goletiani et al Exp Clin Psychopharmacol 200715(5)427-444

Progestin Regimen and Breast Cancer Risk

221551 prescriptions 1994-2005

Lowest risk of breast cancer - estrogen alone

Sequential progestin usage (178) less risk than continuous

combined (RR 244)

Little effect on breast cancer risk if used lt5 years

Lyytinen H1 Pukkala E Ylikorkala O Breast cancer risk in postmenopausal women using

estradiol-progestogen therapy Obstet Gynecol 2009 Jan113(1)65-73

E2 estradiol mic P4 micronized progesterone DHG dydrogesterone synt Prog synthetic progestins (mainly nomegestrol acetate promegestone chlormadinone acetate cyproterone acetate medrogestone)

Relative risks for invasive breast cancer by type of HRT and type of progestagen compared with HRT never-use (E3N cohort study N=80377)

Fournier A et al Breast Cancer Res Treat 2008 107 103-111

0

02

04

06

08

1

12

14

16

18

2

E2 alone E2 + mic P4 E2 + DHG E2 + synth Prog

130

100

110

160

Simon 2015

6

Pathogenic Sequence of Vascular AgingNo HRT Adventitia

Media

Fatty StreakPlaque

InternalElasticLamina

Necrotic Core

Plaque

FibrousCap

FibrousCap

Plaque Necrotic Core

Plaque

FibrousCap

MMP-9

EPAT = HRT Early amp Continued

WELL-HART = HRT Late

HRT

Age 35-45 years Age 45-55 years Age 55-65 years Age gt65 years

HRT

Mural Thrombus

Hodis HN et al N Eng J Med 2003349535ndash545

ELITE - Design

Study design Single-center randomized double-blinded placebo-controlled trial with a 2 x 2 factorial design

Subjects 643 healthy recently postmenopausal (lt6 years) and remotely postmenopausal women (gt10 years) without preexisting CVD and diabetes mellitus

Intervention Oral micronized 17β-estradiol 1 mgd (+ 45 mg vaginal micronized progesterone gel x 10 days every month in women with a uterus) Or Matching Placebos

Follow-up Every month for the first 6 months and then every 2 months for 5-6 years

Funding NIH ndash National Institute on Aging (R01AG-024154)

ELITE TRIAL RESULTS

Hodis HN Mack WJ Henderson VW et al Vascular Effects of Early versus Late

Postmenopausal Treatment with Estradiol N Engl J Med 20163741221-31

Hodis HN Mack WJ Henderson VW et al Vascular Effects of Early versus Late

Postmenopausal Treatment with Estradiol N Engl J Med 20163741221-31

All Ages

gt10 years since menopause

gt60 years old

lt10 years since menopause

lt60 years old

025 050 10 15 20

Relative Risk (95 CI)

099 (088-111)

068 (048-096)

103 (091-116)

CHD Events Associated with HRT inYounger and Older Women

Meta-analysis of 23 Randomized Controlled Trials (191340 patient-years)

Salpeter S et al J Gen Intern Med 200621363-366

Mortality

Simon 2015

7

All-Cause Mortality Associated with HRT in Younger and Older Women Meta-analysis of 30 Randomized

Controlled Trials (119118 patient-years)

025 050 10 15 20

Relative Risk (95 CI)

098 (087-118)

061 (039-095)

103 (090-118)

Salpeter SR et al J Gen Intern Med 200419791-804

All Ages

gt60 years old

Mean age = 66 years

lt60 years old

Mean age = 54 years

gt10 years since menopause

gt60 years old

lt10 years since menopause

lt60 years old

025 050 10 15

Relative Risk (95 CI)

070 (052-095)

106 (095-118)

Cochrane Meta-analysisAll-Cause Mortality from Randomized Controlled Trials of HRT in Younger and Older Postmenopausal Women

Boardman HMP et al Cochrane Database of Systemic Reviews 2015 Issue 3CD002229 DOI 10100214651858CD002229pub4

Bayesian Meta-Analysis of HRT and All-Cause Mortality in Younger (mean age 545 years) Postmenopausal Women

19 randomized controlled trials- 16283 women- 83043 patient-years- mean 51 years (1-68 years)

8 prospective observational studies- 212717 women- 2935495 patient-years- 138 years (6-22 years)

Randomized controlled trials andobservational studies combined

025 050 10 15 20

Relative Risk (95 CI)

073 (052-096)

072 (062-082)

078 (069-090)

Salpeter SR et al Am J Med 20091221016-1022

Sex-Specificity of Primary Prevention Therapies

Primary vs Secondary Prevention of CHD with Lipid-Lowering Therapy in Women

025 050 10 15 20

Relative Risk (95 CI)

CHD events

Non-fatal MI

CHD mortality

Total mortality

080 (071-091)

074 (055-100)

Secondary Prevention8 RCTs

8272 Women

073 (059-090)

100 (077-129)

025 050 10 15 20

Relative Risk (95 CI)

089 (069-109)

107 (047-204)

061 (022-168)

095 (062-146)

Primary Prevention6 RCTs

11435 Women

Walsh JME et al JAMA 20042912243-2252

Meta-Analysis of Primary Prevention of

CHD with Statin Therapy in Women vs Men

025 050 10 15 20

Relative Risk (95 CI)

072 (061-086)N=26921

095 (086-106)N=26921

Men

025 050 10 15 20

Relative Risk (95 CI)

CHD events

Total mortality

079 (056-113)N=20817

091 (076-108)N=20817

Women

Brugts JJ et al BMJ 2009338b2376

Simon 2015

8

Meta-Analysis of Primary Prevention of

CHD with Statin Therapy in Women vs Men

025 050 10 15 20

Relative Risk (95 CI)

055 (041-075)N=28346

093 (083-104)N=20426

Men

025 050 10 15 20

Relative Risk (95 CI)

CHD events

Total mortality

095 (078-116)N=13346

096 (081-113)N=11849

Women

Petretta M et al Int J Cardiol 201013825-31

Breast Cancer in Randomized Controlled Trials of Hormone and Statin Therapy

TherapyPlacebo Study

-21005 (053)5 (055)

8097-159124199 (042)150 (033)

CEE+MPA

WHI-EP

12077-21913032 (057)25 (045)HERS

15078-34916518 (038)11 (023)

STATIN

PROSPER

95 CI

No of Patients (Annualized )

No Additional Breast Cancer Cases per 10000 Women per

Year of TherapyRelative Risk

15062-33614413 (050)9 (035)AFCAPS

5046-4521447 (017)5 (011)4S-10 y fu

77248-5980121712 (082)1 (007)CARE

0042-24210010 (022)10 (022)LIPID

-2058-14809334 (028)37 (030)ALLHAT-LLT

-8065-104082129 (034)161 (042)

CEE alone

WHI-E

030-350

17B-E2 alone

WEST

-10049-11307538 (030)51 (040)HPS

025 050 10 15 20

Relative Risk (95 CI)

MI

Stroke

Total mortality

101 (084-121)N=51342

094 (074-119)N=51342

Women

083 (070-097)N=51342

025 050 10 15 20

Relative Risk (95 CI)

068 (054-086)N=44114

093 (085-103)N=44114

Men

113 (096-133)N=44114

Meta-Analysis of Primary Prevention of CVD with Aspirin in Women vs Men

Berger JS et al JAMA 2006295306-313

Are Transdermal Preparations Safer

CHDbull In a Danish national registry significantly lower risk of MI was found with

the transdermal route than with oral unopposed estrogen (P=004)2 STROKEbull In a nested case-control study from the UK General Practice Research

database (n=15710) the risk of stroke was not increased with low-dose transdermal estrogen (50 mcg) but did increase with higher transdermal doses and oral therapies3

VTEbull In a French systematic review and meta-analysis the risk of first-time

VTE was increased in oral estrogen users but not in transdermal estrogen users (OR 25 [19ndash34] for oral 12 [09ndash17] for transdermal)1

1 Canonico et al BMJ 2008 336 (7655) 1227-1231 2 Loslashkkegaard E Andreasen AH Jacobsen RK et al Eur Heart J 2008 29 2660-83 Renoux C et al BMJ 2010340c2519

Adjusted Incidence Rate Ratio of CVD Events

Transdermal ET vs Oral ET (sensitivity analysis)Increased Risk of Venous Thrombosis with

Conjugated Equine Estrogens (CEE) vs Estradiol

Smith NL Blondon M Wiggins KL et al Lower Risk of Cardiovascular Events in Postmenopausal Women Taking Oral Estradiol Compared With Oral Conjugated Equine Estrogens JAMA Intern Med 2014174(1)25-34

Simon 2015

9

Transdermal estrogen and

change in body weight or BMI

bull ldquoOne crossover study noted greater fat gain with

oral vs transdermal estrogen results that are

supported by clinical datardquo

Santen RJ Postmenopausal Hormone Therapy An Endocrine Society Scientific Statement JCEM201095S1S1-S66

Breast Cancer

The HeadlinesThe Womenrsquos Health Initiative Results (E + P)

41 Increase in Strokes 29 Increase in Heart Attacks 100 Increase in Venous Thromboembolism 22 Increase in Total CV Disease

26 Increase in Breast Cancer (331000 increased to 411000 for each year)

37 Decrease in Colorectal Cancer 33 Decrease in Hip Fracture 24 Decrease in Total Fractures No Difference in All Cause Mortality

None 12304 114 vs 102 106 081-138

lt5 yrs 3005 32 vs 15 213 115-394

5-10 yrs 783 11 vs 2 461 101-2102

gt10 yrs 515 9 vs 5 181 060-543

YRS N HT vs PBO HR 95 CI

WHI Breast Cancer

by Years of Prior Use (E + P) [2002]

Writing Group for Womenrsquos Health Initiative Investigators JAMA 2002 288

0

001

002

003

004

0 1 2 3 4 5 6 7

WHI E+P Trial No Effect of E+P on Risk of In Situ Breast Cancer

Cu

mu

lati

ve

Pro

port

ion

Time (years)

Chlebowski RT et al JAMA 2003289(24)3243-3253

Placebo

EP

HR = 118

95 CI = 077ndash182

Stefanick ML et al JAMA 2006295(14)1647-1657Permission to reprint requested from the American Medical Association

Cumulative Hazard for Total Invasive and In Situ Breast CancerEstrogen-Only

Simon 2015

10

The Gap or Timing Hypothesis (earlier ldquobetterrdquo later ldquoworserdquo)

This Gap Hypothesis also seems to apply to

Mood1

Dementia2

Ischemic Stroke3

Mild cognitive impairment4

Parkinsonrsquos Disease5

1Soares CN Maki PM Menopausal transition mood and cognition an integrated view to close the gaps Menopause 2010 17 (4) 812-8142Rocca WA Grossardt BR Shuster LT Stewart EA Hysterectomy Oophorectomy Estrogen and the Risk of Dementia Neurodegener Dis 2012 Jan 21 [Epub ahead of print]3Rocca WA Grossardt BR Miller VM Shuster LT Brown RD Jr Premature menopause or early menopause and risk of ischemic stroke Menopause 2012 Mar19(3)272-74Rocca WA Grossardt BR Shuster LT Oophorectomy menopause estrogen treatment and cognitive aging clinical evidence for a window of opportunity Brain Res

2011 Mar 161379188-98 Epub 2010 Oct 18 Review5Rocca WA Bower JH Maraganore DM Ahlskog JE Grossardt BR de Andrade M Melton LJ 3rd Increased risk of parkinsonism in women who underwent oophorectomy

before menopause Neurology 2008 Jan 1570(3)200-9 Epub 2007 Aug 29

Outcomes WHI-E RUTH

n= 10739 n=10101

mean age 636 years 675 years

mean follow-up 68 years 56 years

No cases10000 womenyear of treatment

CHD -5 -7

Stroke 12 (8) 9

VTE 7 11

PE 4 4

DVT 6 6

Breast cancer -8 -8

Bone fracture -56 -15

Hsia et al Arch Intern Med 2006166357-365

Writing Group for the Womens Health Initiative Investigators JAMA 20042911701-1712

Curb JD et al Arch Intern Med 2006166772-780

Stefanick ML et al JAMA 20062951647-1657

RUTH New Engl J Med 2006355125-137

WHI-E in Perspective (Not Head-To-Head)

Does the type of

progestogen matter

Is There a Difference Among Progestins

bull Comparative data is insufficient

bull Current research is ongoing in light of WHI findings

that suggested possible harm from progesterone (EPT

compared with ET)

bull PEPI a large RCT suggested micronized

progesterone has less negative impact on lipids

bull Small trials suggest VTE with micronized

progesterone

bull Caveat formulated in a peanut oil suspension so

ask about peanut allergies

Canonico et al Circulation 2007115(7)840-845

Goletiani et al Exp Clin Psychopharmacol 200715(5)427-444

Progestin Regimen and Breast Cancer Risk

221551 prescriptions 1994-2005

Lowest risk of breast cancer - estrogen alone

Sequential progestin usage (178) less risk than continuous

combined (RR 244)

Little effect on breast cancer risk if used lt5 years

Lyytinen H1 Pukkala E Ylikorkala O Breast cancer risk in postmenopausal women using

estradiol-progestogen therapy Obstet Gynecol 2009 Jan113(1)65-73

E2 estradiol mic P4 micronized progesterone DHG dydrogesterone synt Prog synthetic progestins (mainly nomegestrol acetate promegestone chlormadinone acetate cyproterone acetate medrogestone)

Relative risks for invasive breast cancer by type of HRT and type of progestagen compared with HRT never-use (E3N cohort study N=80377)

Fournier A et al Breast Cancer Res Treat 2008 107 103-111

0

02

04

06

08

1

12

14

16

18

2

E2 alone E2 + mic P4 E2 + DHG E2 + synth Prog

130

100

110

160

Simon 2015

7

All-Cause Mortality Associated with HRT in Younger and Older Women Meta-analysis of 30 Randomized

Controlled Trials (119118 patient-years)

025 050 10 15 20

Relative Risk (95 CI)

098 (087-118)

061 (039-095)

103 (090-118)

Salpeter SR et al J Gen Intern Med 200419791-804

All Ages

gt60 years old

Mean age = 66 years

lt60 years old

Mean age = 54 years

gt10 years since menopause

gt60 years old

lt10 years since menopause

lt60 years old

025 050 10 15

Relative Risk (95 CI)

070 (052-095)

106 (095-118)

Cochrane Meta-analysisAll-Cause Mortality from Randomized Controlled Trials of HRT in Younger and Older Postmenopausal Women

Boardman HMP et al Cochrane Database of Systemic Reviews 2015 Issue 3CD002229 DOI 10100214651858CD002229pub4

Bayesian Meta-Analysis of HRT and All-Cause Mortality in Younger (mean age 545 years) Postmenopausal Women

19 randomized controlled trials- 16283 women- 83043 patient-years- mean 51 years (1-68 years)

8 prospective observational studies- 212717 women- 2935495 patient-years- 138 years (6-22 years)

Randomized controlled trials andobservational studies combined

025 050 10 15 20

Relative Risk (95 CI)

073 (052-096)

072 (062-082)

078 (069-090)

Salpeter SR et al Am J Med 20091221016-1022

Sex-Specificity of Primary Prevention Therapies

Primary vs Secondary Prevention of CHD with Lipid-Lowering Therapy in Women

025 050 10 15 20

Relative Risk (95 CI)

CHD events

Non-fatal MI

CHD mortality

Total mortality

080 (071-091)

074 (055-100)

Secondary Prevention8 RCTs

8272 Women

073 (059-090)

100 (077-129)

025 050 10 15 20

Relative Risk (95 CI)

089 (069-109)

107 (047-204)

061 (022-168)

095 (062-146)

Primary Prevention6 RCTs

11435 Women

Walsh JME et al JAMA 20042912243-2252

Meta-Analysis of Primary Prevention of

CHD with Statin Therapy in Women vs Men

025 050 10 15 20

Relative Risk (95 CI)

072 (061-086)N=26921

095 (086-106)N=26921

Men

025 050 10 15 20

Relative Risk (95 CI)

CHD events

Total mortality

079 (056-113)N=20817

091 (076-108)N=20817

Women

Brugts JJ et al BMJ 2009338b2376

Simon 2015

8

Meta-Analysis of Primary Prevention of

CHD with Statin Therapy in Women vs Men

025 050 10 15 20

Relative Risk (95 CI)

055 (041-075)N=28346

093 (083-104)N=20426

Men

025 050 10 15 20

Relative Risk (95 CI)

CHD events

Total mortality

095 (078-116)N=13346

096 (081-113)N=11849

Women

Petretta M et al Int J Cardiol 201013825-31

Breast Cancer in Randomized Controlled Trials of Hormone and Statin Therapy

TherapyPlacebo Study

-21005 (053)5 (055)

8097-159124199 (042)150 (033)

CEE+MPA

WHI-EP

12077-21913032 (057)25 (045)HERS

15078-34916518 (038)11 (023)

STATIN

PROSPER

95 CI

No of Patients (Annualized )

No Additional Breast Cancer Cases per 10000 Women per

Year of TherapyRelative Risk

15062-33614413 (050)9 (035)AFCAPS

5046-4521447 (017)5 (011)4S-10 y fu

77248-5980121712 (082)1 (007)CARE

0042-24210010 (022)10 (022)LIPID

-2058-14809334 (028)37 (030)ALLHAT-LLT

-8065-104082129 (034)161 (042)

CEE alone

WHI-E

030-350

17B-E2 alone

WEST

-10049-11307538 (030)51 (040)HPS

025 050 10 15 20

Relative Risk (95 CI)

MI

Stroke

Total mortality

101 (084-121)N=51342

094 (074-119)N=51342

Women

083 (070-097)N=51342

025 050 10 15 20

Relative Risk (95 CI)

068 (054-086)N=44114

093 (085-103)N=44114

Men

113 (096-133)N=44114

Meta-Analysis of Primary Prevention of CVD with Aspirin in Women vs Men

Berger JS et al JAMA 2006295306-313

Are Transdermal Preparations Safer

CHDbull In a Danish national registry significantly lower risk of MI was found with

the transdermal route than with oral unopposed estrogen (P=004)2 STROKEbull In a nested case-control study from the UK General Practice Research

database (n=15710) the risk of stroke was not increased with low-dose transdermal estrogen (50 mcg) but did increase with higher transdermal doses and oral therapies3

VTEbull In a French systematic review and meta-analysis the risk of first-time

VTE was increased in oral estrogen users but not in transdermal estrogen users (OR 25 [19ndash34] for oral 12 [09ndash17] for transdermal)1

1 Canonico et al BMJ 2008 336 (7655) 1227-1231 2 Loslashkkegaard E Andreasen AH Jacobsen RK et al Eur Heart J 2008 29 2660-83 Renoux C et al BMJ 2010340c2519

Adjusted Incidence Rate Ratio of CVD Events

Transdermal ET vs Oral ET (sensitivity analysis)Increased Risk of Venous Thrombosis with

Conjugated Equine Estrogens (CEE) vs Estradiol

Smith NL Blondon M Wiggins KL et al Lower Risk of Cardiovascular Events in Postmenopausal Women Taking Oral Estradiol Compared With Oral Conjugated Equine Estrogens JAMA Intern Med 2014174(1)25-34

Simon 2015

9

Transdermal estrogen and

change in body weight or BMI

bull ldquoOne crossover study noted greater fat gain with

oral vs transdermal estrogen results that are

supported by clinical datardquo

Santen RJ Postmenopausal Hormone Therapy An Endocrine Society Scientific Statement JCEM201095S1S1-S66

Breast Cancer

The HeadlinesThe Womenrsquos Health Initiative Results (E + P)

41 Increase in Strokes 29 Increase in Heart Attacks 100 Increase in Venous Thromboembolism 22 Increase in Total CV Disease

26 Increase in Breast Cancer (331000 increased to 411000 for each year)

37 Decrease in Colorectal Cancer 33 Decrease in Hip Fracture 24 Decrease in Total Fractures No Difference in All Cause Mortality

None 12304 114 vs 102 106 081-138

lt5 yrs 3005 32 vs 15 213 115-394

5-10 yrs 783 11 vs 2 461 101-2102

gt10 yrs 515 9 vs 5 181 060-543

YRS N HT vs PBO HR 95 CI

WHI Breast Cancer

by Years of Prior Use (E + P) [2002]

Writing Group for Womenrsquos Health Initiative Investigators JAMA 2002 288

0

001

002

003

004

0 1 2 3 4 5 6 7

WHI E+P Trial No Effect of E+P on Risk of In Situ Breast Cancer

Cu

mu

lati

ve

Pro

port

ion

Time (years)

Chlebowski RT et al JAMA 2003289(24)3243-3253

Placebo

EP

HR = 118

95 CI = 077ndash182

Stefanick ML et al JAMA 2006295(14)1647-1657Permission to reprint requested from the American Medical Association

Cumulative Hazard for Total Invasive and In Situ Breast CancerEstrogen-Only

Simon 2015

10

The Gap or Timing Hypothesis (earlier ldquobetterrdquo later ldquoworserdquo)

This Gap Hypothesis also seems to apply to

Mood1

Dementia2

Ischemic Stroke3

Mild cognitive impairment4

Parkinsonrsquos Disease5

1Soares CN Maki PM Menopausal transition mood and cognition an integrated view to close the gaps Menopause 2010 17 (4) 812-8142Rocca WA Grossardt BR Shuster LT Stewart EA Hysterectomy Oophorectomy Estrogen and the Risk of Dementia Neurodegener Dis 2012 Jan 21 [Epub ahead of print]3Rocca WA Grossardt BR Miller VM Shuster LT Brown RD Jr Premature menopause or early menopause and risk of ischemic stroke Menopause 2012 Mar19(3)272-74Rocca WA Grossardt BR Shuster LT Oophorectomy menopause estrogen treatment and cognitive aging clinical evidence for a window of opportunity Brain Res

2011 Mar 161379188-98 Epub 2010 Oct 18 Review5Rocca WA Bower JH Maraganore DM Ahlskog JE Grossardt BR de Andrade M Melton LJ 3rd Increased risk of parkinsonism in women who underwent oophorectomy

before menopause Neurology 2008 Jan 1570(3)200-9 Epub 2007 Aug 29

Outcomes WHI-E RUTH

n= 10739 n=10101

mean age 636 years 675 years

mean follow-up 68 years 56 years

No cases10000 womenyear of treatment

CHD -5 -7

Stroke 12 (8) 9

VTE 7 11

PE 4 4

DVT 6 6

Breast cancer -8 -8

Bone fracture -56 -15

Hsia et al Arch Intern Med 2006166357-365

Writing Group for the Womens Health Initiative Investigators JAMA 20042911701-1712

Curb JD et al Arch Intern Med 2006166772-780

Stefanick ML et al JAMA 20062951647-1657

RUTH New Engl J Med 2006355125-137

WHI-E in Perspective (Not Head-To-Head)

Does the type of

progestogen matter

Is There a Difference Among Progestins

bull Comparative data is insufficient

bull Current research is ongoing in light of WHI findings

that suggested possible harm from progesterone (EPT

compared with ET)

bull PEPI a large RCT suggested micronized

progesterone has less negative impact on lipids

bull Small trials suggest VTE with micronized

progesterone

bull Caveat formulated in a peanut oil suspension so

ask about peanut allergies

Canonico et al Circulation 2007115(7)840-845

Goletiani et al Exp Clin Psychopharmacol 200715(5)427-444

Progestin Regimen and Breast Cancer Risk

221551 prescriptions 1994-2005

Lowest risk of breast cancer - estrogen alone

Sequential progestin usage (178) less risk than continuous

combined (RR 244)

Little effect on breast cancer risk if used lt5 years

Lyytinen H1 Pukkala E Ylikorkala O Breast cancer risk in postmenopausal women using

estradiol-progestogen therapy Obstet Gynecol 2009 Jan113(1)65-73

E2 estradiol mic P4 micronized progesterone DHG dydrogesterone synt Prog synthetic progestins (mainly nomegestrol acetate promegestone chlormadinone acetate cyproterone acetate medrogestone)

Relative risks for invasive breast cancer by type of HRT and type of progestagen compared with HRT never-use (E3N cohort study N=80377)

Fournier A et al Breast Cancer Res Treat 2008 107 103-111

0

02

04

06

08

1

12

14

16

18

2

E2 alone E2 + mic P4 E2 + DHG E2 + synth Prog

130

100

110

160

Simon 2015

8

Meta-Analysis of Primary Prevention of

CHD with Statin Therapy in Women vs Men

025 050 10 15 20

Relative Risk (95 CI)

055 (041-075)N=28346

093 (083-104)N=20426

Men

025 050 10 15 20

Relative Risk (95 CI)

CHD events

Total mortality

095 (078-116)N=13346

096 (081-113)N=11849

Women

Petretta M et al Int J Cardiol 201013825-31

Breast Cancer in Randomized Controlled Trials of Hormone and Statin Therapy

TherapyPlacebo Study

-21005 (053)5 (055)

8097-159124199 (042)150 (033)

CEE+MPA

WHI-EP

12077-21913032 (057)25 (045)HERS

15078-34916518 (038)11 (023)

STATIN

PROSPER

95 CI

No of Patients (Annualized )

No Additional Breast Cancer Cases per 10000 Women per

Year of TherapyRelative Risk

15062-33614413 (050)9 (035)AFCAPS

5046-4521447 (017)5 (011)4S-10 y fu

77248-5980121712 (082)1 (007)CARE

0042-24210010 (022)10 (022)LIPID

-2058-14809334 (028)37 (030)ALLHAT-LLT

-8065-104082129 (034)161 (042)

CEE alone

WHI-E

030-350

17B-E2 alone

WEST

-10049-11307538 (030)51 (040)HPS

025 050 10 15 20

Relative Risk (95 CI)

MI

Stroke

Total mortality

101 (084-121)N=51342

094 (074-119)N=51342

Women

083 (070-097)N=51342

025 050 10 15 20

Relative Risk (95 CI)

068 (054-086)N=44114

093 (085-103)N=44114

Men

113 (096-133)N=44114

Meta-Analysis of Primary Prevention of CVD with Aspirin in Women vs Men

Berger JS et al JAMA 2006295306-313

Are Transdermal Preparations Safer

CHDbull In a Danish national registry significantly lower risk of MI was found with

the transdermal route than with oral unopposed estrogen (P=004)2 STROKEbull In a nested case-control study from the UK General Practice Research

database (n=15710) the risk of stroke was not increased with low-dose transdermal estrogen (50 mcg) but did increase with higher transdermal doses and oral therapies3

VTEbull In a French systematic review and meta-analysis the risk of first-time

VTE was increased in oral estrogen users but not in transdermal estrogen users (OR 25 [19ndash34] for oral 12 [09ndash17] for transdermal)1

1 Canonico et al BMJ 2008 336 (7655) 1227-1231 2 Loslashkkegaard E Andreasen AH Jacobsen RK et al Eur Heart J 2008 29 2660-83 Renoux C et al BMJ 2010340c2519

Adjusted Incidence Rate Ratio of CVD Events

Transdermal ET vs Oral ET (sensitivity analysis)Increased Risk of Venous Thrombosis with

Conjugated Equine Estrogens (CEE) vs Estradiol

Smith NL Blondon M Wiggins KL et al Lower Risk of Cardiovascular Events in Postmenopausal Women Taking Oral Estradiol Compared With Oral Conjugated Equine Estrogens JAMA Intern Med 2014174(1)25-34

Simon 2015

9

Transdermal estrogen and

change in body weight or BMI

bull ldquoOne crossover study noted greater fat gain with

oral vs transdermal estrogen results that are

supported by clinical datardquo

Santen RJ Postmenopausal Hormone Therapy An Endocrine Society Scientific Statement JCEM201095S1S1-S66

Breast Cancer

The HeadlinesThe Womenrsquos Health Initiative Results (E + P)

41 Increase in Strokes 29 Increase in Heart Attacks 100 Increase in Venous Thromboembolism 22 Increase in Total CV Disease

26 Increase in Breast Cancer (331000 increased to 411000 for each year)

37 Decrease in Colorectal Cancer 33 Decrease in Hip Fracture 24 Decrease in Total Fractures No Difference in All Cause Mortality

None 12304 114 vs 102 106 081-138

lt5 yrs 3005 32 vs 15 213 115-394

5-10 yrs 783 11 vs 2 461 101-2102

gt10 yrs 515 9 vs 5 181 060-543

YRS N HT vs PBO HR 95 CI

WHI Breast Cancer

by Years of Prior Use (E + P) [2002]

Writing Group for Womenrsquos Health Initiative Investigators JAMA 2002 288

0

001

002

003

004

0 1 2 3 4 5 6 7

WHI E+P Trial No Effect of E+P on Risk of In Situ Breast Cancer

Cu

mu

lati

ve

Pro

port

ion

Time (years)

Chlebowski RT et al JAMA 2003289(24)3243-3253

Placebo

EP

HR = 118

95 CI = 077ndash182

Stefanick ML et al JAMA 2006295(14)1647-1657Permission to reprint requested from the American Medical Association

Cumulative Hazard for Total Invasive and In Situ Breast CancerEstrogen-Only

Simon 2015

10

The Gap or Timing Hypothesis (earlier ldquobetterrdquo later ldquoworserdquo)

This Gap Hypothesis also seems to apply to

Mood1

Dementia2

Ischemic Stroke3

Mild cognitive impairment4

Parkinsonrsquos Disease5

1Soares CN Maki PM Menopausal transition mood and cognition an integrated view to close the gaps Menopause 2010 17 (4) 812-8142Rocca WA Grossardt BR Shuster LT Stewart EA Hysterectomy Oophorectomy Estrogen and the Risk of Dementia Neurodegener Dis 2012 Jan 21 [Epub ahead of print]3Rocca WA Grossardt BR Miller VM Shuster LT Brown RD Jr Premature menopause or early menopause and risk of ischemic stroke Menopause 2012 Mar19(3)272-74Rocca WA Grossardt BR Shuster LT Oophorectomy menopause estrogen treatment and cognitive aging clinical evidence for a window of opportunity Brain Res

2011 Mar 161379188-98 Epub 2010 Oct 18 Review5Rocca WA Bower JH Maraganore DM Ahlskog JE Grossardt BR de Andrade M Melton LJ 3rd Increased risk of parkinsonism in women who underwent oophorectomy

before menopause Neurology 2008 Jan 1570(3)200-9 Epub 2007 Aug 29

Outcomes WHI-E RUTH

n= 10739 n=10101

mean age 636 years 675 years

mean follow-up 68 years 56 years

No cases10000 womenyear of treatment

CHD -5 -7

Stroke 12 (8) 9

VTE 7 11

PE 4 4

DVT 6 6

Breast cancer -8 -8

Bone fracture -56 -15

Hsia et al Arch Intern Med 2006166357-365

Writing Group for the Womens Health Initiative Investigators JAMA 20042911701-1712

Curb JD et al Arch Intern Med 2006166772-780

Stefanick ML et al JAMA 20062951647-1657

RUTH New Engl J Med 2006355125-137

WHI-E in Perspective (Not Head-To-Head)

Does the type of

progestogen matter

Is There a Difference Among Progestins

bull Comparative data is insufficient

bull Current research is ongoing in light of WHI findings

that suggested possible harm from progesterone (EPT

compared with ET)

bull PEPI a large RCT suggested micronized

progesterone has less negative impact on lipids

bull Small trials suggest VTE with micronized

progesterone

bull Caveat formulated in a peanut oil suspension so

ask about peanut allergies

Canonico et al Circulation 2007115(7)840-845

Goletiani et al Exp Clin Psychopharmacol 200715(5)427-444

Progestin Regimen and Breast Cancer Risk

221551 prescriptions 1994-2005

Lowest risk of breast cancer - estrogen alone

Sequential progestin usage (178) less risk than continuous

combined (RR 244)

Little effect on breast cancer risk if used lt5 years

Lyytinen H1 Pukkala E Ylikorkala O Breast cancer risk in postmenopausal women using

estradiol-progestogen therapy Obstet Gynecol 2009 Jan113(1)65-73

E2 estradiol mic P4 micronized progesterone DHG dydrogesterone synt Prog synthetic progestins (mainly nomegestrol acetate promegestone chlormadinone acetate cyproterone acetate medrogestone)

Relative risks for invasive breast cancer by type of HRT and type of progestagen compared with HRT never-use (E3N cohort study N=80377)

Fournier A et al Breast Cancer Res Treat 2008 107 103-111

0

02

04

06

08

1

12

14

16

18

2

E2 alone E2 + mic P4 E2 + DHG E2 + synth Prog

130

100

110

160

Simon 2015

9

Transdermal estrogen and

change in body weight or BMI

bull ldquoOne crossover study noted greater fat gain with

oral vs transdermal estrogen results that are

supported by clinical datardquo

Santen RJ Postmenopausal Hormone Therapy An Endocrine Society Scientific Statement JCEM201095S1S1-S66

Breast Cancer

The HeadlinesThe Womenrsquos Health Initiative Results (E + P)

41 Increase in Strokes 29 Increase in Heart Attacks 100 Increase in Venous Thromboembolism 22 Increase in Total CV Disease

26 Increase in Breast Cancer (331000 increased to 411000 for each year)

37 Decrease in Colorectal Cancer 33 Decrease in Hip Fracture 24 Decrease in Total Fractures No Difference in All Cause Mortality

None 12304 114 vs 102 106 081-138

lt5 yrs 3005 32 vs 15 213 115-394

5-10 yrs 783 11 vs 2 461 101-2102

gt10 yrs 515 9 vs 5 181 060-543

YRS N HT vs PBO HR 95 CI

WHI Breast Cancer

by Years of Prior Use (E + P) [2002]

Writing Group for Womenrsquos Health Initiative Investigators JAMA 2002 288

0

001

002

003

004

0 1 2 3 4 5 6 7

WHI E+P Trial No Effect of E+P on Risk of In Situ Breast Cancer

Cu

mu

lati

ve

Pro

port

ion

Time (years)

Chlebowski RT et al JAMA 2003289(24)3243-3253

Placebo

EP

HR = 118

95 CI = 077ndash182

Stefanick ML et al JAMA 2006295(14)1647-1657Permission to reprint requested from the American Medical Association

Cumulative Hazard for Total Invasive and In Situ Breast CancerEstrogen-Only

Simon 2015

10

The Gap or Timing Hypothesis (earlier ldquobetterrdquo later ldquoworserdquo)

This Gap Hypothesis also seems to apply to

Mood1

Dementia2

Ischemic Stroke3

Mild cognitive impairment4

Parkinsonrsquos Disease5

1Soares CN Maki PM Menopausal transition mood and cognition an integrated view to close the gaps Menopause 2010 17 (4) 812-8142Rocca WA Grossardt BR Shuster LT Stewart EA Hysterectomy Oophorectomy Estrogen and the Risk of Dementia Neurodegener Dis 2012 Jan 21 [Epub ahead of print]3Rocca WA Grossardt BR Miller VM Shuster LT Brown RD Jr Premature menopause or early menopause and risk of ischemic stroke Menopause 2012 Mar19(3)272-74Rocca WA Grossardt BR Shuster LT Oophorectomy menopause estrogen treatment and cognitive aging clinical evidence for a window of opportunity Brain Res

2011 Mar 161379188-98 Epub 2010 Oct 18 Review5Rocca WA Bower JH Maraganore DM Ahlskog JE Grossardt BR de Andrade M Melton LJ 3rd Increased risk of parkinsonism in women who underwent oophorectomy

before menopause Neurology 2008 Jan 1570(3)200-9 Epub 2007 Aug 29

Outcomes WHI-E RUTH

n= 10739 n=10101

mean age 636 years 675 years

mean follow-up 68 years 56 years

No cases10000 womenyear of treatment

CHD -5 -7

Stroke 12 (8) 9

VTE 7 11

PE 4 4

DVT 6 6

Breast cancer -8 -8

Bone fracture -56 -15

Hsia et al Arch Intern Med 2006166357-365

Writing Group for the Womens Health Initiative Investigators JAMA 20042911701-1712

Curb JD et al Arch Intern Med 2006166772-780

Stefanick ML et al JAMA 20062951647-1657

RUTH New Engl J Med 2006355125-137

WHI-E in Perspective (Not Head-To-Head)

Does the type of

progestogen matter

Is There a Difference Among Progestins

bull Comparative data is insufficient

bull Current research is ongoing in light of WHI findings

that suggested possible harm from progesterone (EPT

compared with ET)

bull PEPI a large RCT suggested micronized

progesterone has less negative impact on lipids

bull Small trials suggest VTE with micronized

progesterone

bull Caveat formulated in a peanut oil suspension so

ask about peanut allergies

Canonico et al Circulation 2007115(7)840-845

Goletiani et al Exp Clin Psychopharmacol 200715(5)427-444

Progestin Regimen and Breast Cancer Risk

221551 prescriptions 1994-2005

Lowest risk of breast cancer - estrogen alone

Sequential progestin usage (178) less risk than continuous

combined (RR 244)

Little effect on breast cancer risk if used lt5 years

Lyytinen H1 Pukkala E Ylikorkala O Breast cancer risk in postmenopausal women using

estradiol-progestogen therapy Obstet Gynecol 2009 Jan113(1)65-73

E2 estradiol mic P4 micronized progesterone DHG dydrogesterone synt Prog synthetic progestins (mainly nomegestrol acetate promegestone chlormadinone acetate cyproterone acetate medrogestone)

Relative risks for invasive breast cancer by type of HRT and type of progestagen compared with HRT never-use (E3N cohort study N=80377)

Fournier A et al Breast Cancer Res Treat 2008 107 103-111

0

02

04

06

08

1

12

14

16

18

2

E2 alone E2 + mic P4 E2 + DHG E2 + synth Prog

130

100

110

160

Simon 2015

10

The Gap or Timing Hypothesis (earlier ldquobetterrdquo later ldquoworserdquo)

This Gap Hypothesis also seems to apply to

Mood1

Dementia2

Ischemic Stroke3

Mild cognitive impairment4

Parkinsonrsquos Disease5

1Soares CN Maki PM Menopausal transition mood and cognition an integrated view to close the gaps Menopause 2010 17 (4) 812-8142Rocca WA Grossardt BR Shuster LT Stewart EA Hysterectomy Oophorectomy Estrogen and the Risk of Dementia Neurodegener Dis 2012 Jan 21 [Epub ahead of print]3Rocca WA Grossardt BR Miller VM Shuster LT Brown RD Jr Premature menopause or early menopause and risk of ischemic stroke Menopause 2012 Mar19(3)272-74Rocca WA Grossardt BR Shuster LT Oophorectomy menopause estrogen treatment and cognitive aging clinical evidence for a window of opportunity Brain Res

2011 Mar 161379188-98 Epub 2010 Oct 18 Review5Rocca WA Bower JH Maraganore DM Ahlskog JE Grossardt BR de Andrade M Melton LJ 3rd Increased risk of parkinsonism in women who underwent oophorectomy

before menopause Neurology 2008 Jan 1570(3)200-9 Epub 2007 Aug 29

Outcomes WHI-E RUTH

n= 10739 n=10101

mean age 636 years 675 years

mean follow-up 68 years 56 years

No cases10000 womenyear of treatment

CHD -5 -7

Stroke 12 (8) 9

VTE 7 11

PE 4 4

DVT 6 6

Breast cancer -8 -8

Bone fracture -56 -15

Hsia et al Arch Intern Med 2006166357-365

Writing Group for the Womens Health Initiative Investigators JAMA 20042911701-1712

Curb JD et al Arch Intern Med 2006166772-780

Stefanick ML et al JAMA 20062951647-1657

RUTH New Engl J Med 2006355125-137

WHI-E in Perspective (Not Head-To-Head)

Does the type of

progestogen matter

Is There a Difference Among Progestins

bull Comparative data is insufficient

bull Current research is ongoing in light of WHI findings

that suggested possible harm from progesterone (EPT

compared with ET)

bull PEPI a large RCT suggested micronized

progesterone has less negative impact on lipids

bull Small trials suggest VTE with micronized

progesterone

bull Caveat formulated in a peanut oil suspension so

ask about peanut allergies

Canonico et al Circulation 2007115(7)840-845

Goletiani et al Exp Clin Psychopharmacol 200715(5)427-444

Progestin Regimen and Breast Cancer Risk

221551 prescriptions 1994-2005

Lowest risk of breast cancer - estrogen alone

Sequential progestin usage (178) less risk than continuous

combined (RR 244)

Little effect on breast cancer risk if used lt5 years

Lyytinen H1 Pukkala E Ylikorkala O Breast cancer risk in postmenopausal women using

estradiol-progestogen therapy Obstet Gynecol 2009 Jan113(1)65-73

E2 estradiol mic P4 micronized progesterone DHG dydrogesterone synt Prog synthetic progestins (mainly nomegestrol acetate promegestone chlormadinone acetate cyproterone acetate medrogestone)

Relative risks for invasive breast cancer by type of HRT and type of progestagen compared with HRT never-use (E3N cohort study N=80377)

Fournier A et al Breast Cancer Res Treat 2008 107 103-111

0

02

04

06

08

1

12

14

16

18

2

E2 alone E2 + mic P4 E2 + DHG E2 + synth Prog

130

100

110

160

Simon 2015

11

Progestin Routes of Administration

bull Oral

minus Medroxyprogesterone

minus Micronized progesterone

bull Transdermal progestin (combined with estrogen)

bull IUD with levonorgestrol

Levonorgestrel IUD HT for Endometrial ProtectionWildemeersch D Gynecol Endocrinol 2013 Jun29(6)569-73 Epub 2013 Mar 7

Femilis Slim (LNG-IUS releasing 20mcgd LNG)

102 women (part of original contraception trial devel VMS given Estrogen)

Pirimoglu ZM et al J Obstet Gynaecol Res 2011 Oct37(10)1376-81 Epub 2011 May 22

LNG-IUS 20mcgd (+1mg oral Estradiol) vs1 mg 17 beta-estradiol2 mg drospirenone)

30 women fitted with LNG-IUS60 women taking oral HT

Depypere HT et al Eur J Obstet Gynecol Reprod Biol 2010 Dec153(2)176-80 [Bayer Phase 3 Study]

LNG-IUS 20mcgd (Mirena)(+Climara or 1-2mg Estradiol valerate)

168 women eligible for ERT phase (from original study of 348 women using LNG-IUS for contraception at least 9 months

Wildemeersch D et al Maturitas 2007 Jun 2057(2)205-9 Epub 2007 Jan 16

2 consecutive LNG-IUS (First 3 years of Fibroplant 14mcgd followed by 5 years of Femilis Slim 20mcgd)[+ E gel patch or oral]

102 women with severe climacteric symptomsHad used the Fibroplant for 3 years (full lifespan) then received Femilis Slim and were followed out to 5 years

Wildemeersch D et al Gynecol Endocrinol 2005 Jun20(6)336-42

Fibroplant (14mcgd ndash indicated for 3 years use) + estrogen gel or patch

150 women had LNG-IUS placed

Wildemeersch D Janssens D Weyers S Maturitas 2005 Jun 1651(2)207-14

Femilis Slim (20mcgd) + estrogen gel or patch

170 insertions were performed in postmenopausalwomen with median age of age 566 (range 435-803)

Hampton NR et al Hum Reprod 2005 Sep20(9)2653-60 Epub 2005 May 19

LNG-IUS 20mcgd (Mirena)(plus CEE 125mgd)

N= 80 insertionsThe mean age was 479 years (SD 33)

Sturdee DW Rantala ML Colau JC Zahradnik HP Riphagen FE Climacteric 2004 Dec7(4)404-11

LNG-IUS 10mcgd (MLS ndash menopause levonorgestrel system - 28x28mm)

294 menopausal women median age 526 years (range 417-596 years) 90 within 3-5 years of LMP 78 had prior HT

Wildemeersch D Schacht E Wildemeersch P et alMaturitas 2004 May 2848(1)65-70

FibroPlant (LNG-IUS 14mcgd) [+ estrogen-percutaneous oral patch]

N=24 used for 3 years

Wildemeersch D Schacht E Wildemeersch PMaturitas 2003 Mar 2844(3)237-45

FibroPlant-LNG-IUS 14 mcgd [+percutaneous Oestrogel 15 mg daily]

Eighty-three insertions in perimenopausal women and 58 in postmenopausal women (total=141)

Raudaskoski T Tapanainen J Tomaacutes E et al BJOG 2002 Feb109(2)136-44

LNG-IUS 10mcgd (Bayer Menopause Levo System 28x28mm) LNG-IUS 20mcgd (Mirena) MPA [+ 2mg E2V]

N=54 (10mcgd LNG-IUS) N=56 Mirena N=53 MPA

Varila E Wahlstroumlm T Rauramo I Fertil Steril 2001 Nov76(5)969-73

LNG-IUS 20mcgd (Mirena) 39 completed 12 months (LNG-IUS + Estrogen) After 5 years 32 still using the LNG IUS 31 consented to further study 29 still on ERT at 5yr Mean age = 60 years (SD 42)

Wildemeersch D Schacht E Maturitas 2000 Jul 3136(1)63-8

Fibroplant LNG-IUS10mcgd and a 14mcgd

N=11 (10mcgd)N=19 (14mcgd)

Suvanto-Luukkonen E Malinen H Sundstroumlm H et al Acta Obstet Gynecol Scand 1998 Aug77(7)758-63

(20mcgd LNG-IUD - Mirena) (n=18) progesterone 100 mg po daily (n= 19) or vaginally (n=15) days 1-25 calendarmo

N=18 recvrsquod LNG-IUS (Mirena) 2 discontinued

CONCLUSION The levonorgestrel-releasing intrauterine system may

have a protective effect against endometrial malignant transformation

Using the levonorgestrel-releasing intrauterine system for treatment of

menorrhagia during reproductive years was associated with a lower

incidence of endometrial ovarian pancreatic and lung cancers than

expected Levonorgestrel-releasing intrauterine system use was

associated with a higher than expected incidence of breast cancer

Soini T1 Hurskainen R Greacutenman S et al Cancer risk in women using the levonorgestrel-releasing intrauterine system in Finland

Obstet Gynecol 2014 Aug124(2 Pt 1)292-9

bull SERM-Bazedoxifene (BZD) coupled with CEE

bull At 045 mg or 0625 mg CEE with 20mg BZD found to be effective and safe treatment for menopausal vasomotor symptoms and osteoporosis prevention in women with intact uterus1

bull BZD competitively inhibits binding of 17B-estradiol protecting the endometrium2

bull No need for progestin

bull Current marketed dose CEE 045 with BZD 20mg daily

bull Not currently FDA approved for GSMVVA

1Pinkerton JV Utian WU Constatine GD et al Relief of vasomotor symptoms with use of TSEC containing BZDCE a randomized controlled trial Menopause 2009161116-1124

2Lobo RA Pinkerton JV Gass M et al Evaluation of BZDCE for the treatment of menopausal symptoms and effects on metabolic bone parameters and overall safety profile Fertil Steril 2009921025-1038

Conjugated estrogensbazedoxifene (Duavee) for menopausal symptoms and prevention of osteoporosis Med Lett Drugs Ther 2014 Apr 2856(1441)33-4

Tissue Selective Estrogen Complex (TSEC)

Effects of BazedoxifeneCEE on

menopausal symptoms Reduction in number of hot flashes up 80

Reduction in severity up to 54

Early onset of action (23 weeks)

Persistence of effect up to 2 years

Increased superficial cells reduced parabasal cells improved

vaginal pH (not FDA approved for VVAGSM)

Decreased dyspareunia (not FDA approved for VVAGSM)

Improved sexual domain on MENQOL

Improvement of sleep and HR QoL over 1 year

Pinkerton JV et al Climacteric 2012

Bachmann G et al Climacteric 2010

Lobo et al RA Fertil Steril 2009

Kagan R et al Menopause 2010

not FDA approved for treatment of

vulvovaginal atrophy dyspareunia sexual

dysfunction sleep or QoL

BazedoxifeneCEE-Overall Safety

Profile and other effects No increase in DVTrsquos MI or strokes

No difference in cancers from placebo group

Acceptable endometrial safety (lt1 hyperplasia)

High rates of amenorrhea

Decreased breast pain

Neutral effects on breast density at 45 mg20 mg marketed dose

Lobo RA Fertil Steril 2009

Archer DF et al Fertil Steril 2009

Pickar JH et al Fertil Steril 2009

Simon 2015

12

WHI E+P Evolving Conclusions 2002

ldquoResults from WHI indicate that the combined

postmenopausal hormones CEE 0625 mgd plus

MPA 25 mgd should not be initiated or continued for

the primary prevention of CHD In addition the

substantial risks for cardiovascular disease and breast

cancer must be weighed against the benefit for fracture

in selecting from the available agents to prevent

osteoporosisrdquo

Rossouw JE et al JAMA 2002288321-333

WHI E+P Evolving Conclusions 2003

ldquoThese conclusions are consistent with those of recently

published guidelines The trial did not address the role of

estrogen plus progestin for the short-term treatment of

menopausal symptoms which remains the only clear

indication for the use of this regimenhellip Women with

indications for treatment such as menopausal symptoms

need to consider with their clinicians the suggestion of a slight

overall increase in the risk of CHD and information on the risks

of other outcomes in making decisions about the use of

estrogen plus progestin therapyrdquo

Manson JE et al N Engl J Med 2003349523-534

WHI E+P Evolving Conclusions 2007

ldquoThese analyses although not definitive suggest that the health consequences of hormone therapy may vary by distance from menopause with no apparent increase in CHD risk for women close to menopause and particularly high risks in women who are distant from menopausehellip

We did not identify any subgroup with reduced risk of CHD although total mortality was reduced among women aged 50 to 59 yearsrdquo

Rossouw JE et al JAMA 20072971465-1477

Aftermath of WHI ndash Fracture Data

Significantly increased age-adjusted osteoporosis-related fractures in 2004 - 2005 versus 2000 ndash 2001

Islam S Menopause 2009 16 77-83

Longitudinal observation of 80955 PM women from 2002 followed for 65 years hip fractures increased in those discontinuing HT versus those staying on HT

HR 155 (136-177) ndash began within 2 yrsKarim R Menopause 2011 18 1172-7

And What if You Stophellip

Mikkola TS Tuomikoski P Lyytinen H et al Increased cardiovascular mortality risk in women discontinuing

postmenopausal hormone therapy [published online ahead of print September 28 2015] J Clin Endocrinol Metab

MEN

WOMEN

Kindig D

Health

Affairs

32 451-8

2013

Simon 2015

13

So When Your Menopausal Patients Are

Get Mixed Signals About Hormone Therapyhellip

Conclusion

Compared with placebo the risks associated with HT in early menopausal women are statistically non-significant HT risks are rare and even more rare (lt11000 women per year of treatment) when initiated in women who are lt60 years of age andor lt10 years since menopause

The magnitude and type of risks associated with HT are less than or similar to other commonly used medications and therapies

HT reduces all-cause mortality CHD fractures and new onset diabetes mellitus and thus the benefits of HT far outweigh the risks

HT significantly reduced fractures in an unselected population of women (ie without osteoporosis or prior fractures) and is the most effective therapy for significantly reducing menopausal symptoms (vasomotor and vulvovaginal atrophy)

ldquoWe enter the world through

the brim of the pelvis and

frequently exit by the neck of

the femurrdquo

CA Newhall MD

Suggested Readingbull Pollycove R Naftolin F and Simon JA The evolutionary origin and significance of

Menopause Menopause 2011 Mar18(3)336-42

bull Lobo RA Where Are We 10 Years After the Womenrsquos Health Initiative J Clin Endocrinol

Metab 2013 May98(5)1771-80

bull Hodis HN Mack WJ The timing hypothesis and hormone replacement therapy a

paradigm shift in the primary prevention of coronary heart disease in women Part 1

comparison of therapeutic efficacy J Am Geriatr Soc 2013 Jun61(6)1005-10

bull Hodis HN Mack WJ The timing hypothesis and hormone replacement therapy a

paradigm shift in the primary prevention of coronary heart disease in women Part 2

comparative risks J Am Geriatr Soc 2013 Jun61(6)1011-1018

bull Gurney EP Nachtigall MJ Nachtigall LE Naftolin F The Womens Health Initiative trial

and related studies 10 years later A clinicians view J Steroid Biochem Mol Biol 2014

Jul1424-11

bull Simon JA What if the Womens Health Initiative had used transdermal estradiol and oral

progesterone instead Menopause 2014 Jul21(7)769-83

bull Sarrel P Portman D Lefebvre P et al Incremental direct and indirect costs of untreated

vasomotor symptoms Menopause 2015 Mar22(3)260-6

bull Manson JE Kaunitz AM Menopause Management mdash Getting Clinical Care Back on

Track N Engl J Med 2016 374(9) 803-806

Simon 2015

12

WHI E+P Evolving Conclusions 2002

ldquoResults from WHI indicate that the combined

postmenopausal hormones CEE 0625 mgd plus

MPA 25 mgd should not be initiated or continued for

the primary prevention of CHD In addition the

substantial risks for cardiovascular disease and breast

cancer must be weighed against the benefit for fracture

in selecting from the available agents to prevent

osteoporosisrdquo

Rossouw JE et al JAMA 2002288321-333

WHI E+P Evolving Conclusions 2003

ldquoThese conclusions are consistent with those of recently

published guidelines The trial did not address the role of

estrogen plus progestin for the short-term treatment of

menopausal symptoms which remains the only clear

indication for the use of this regimenhellip Women with

indications for treatment such as menopausal symptoms

need to consider with their clinicians the suggestion of a slight

overall increase in the risk of CHD and information on the risks

of other outcomes in making decisions about the use of

estrogen plus progestin therapyrdquo

Manson JE et al N Engl J Med 2003349523-534

WHI E+P Evolving Conclusions 2007

ldquoThese analyses although not definitive suggest that the health consequences of hormone therapy may vary by distance from menopause with no apparent increase in CHD risk for women close to menopause and particularly high risks in women who are distant from menopausehellip

We did not identify any subgroup with reduced risk of CHD although total mortality was reduced among women aged 50 to 59 yearsrdquo

Rossouw JE et al JAMA 20072971465-1477

Aftermath of WHI ndash Fracture Data

Significantly increased age-adjusted osteoporosis-related fractures in 2004 - 2005 versus 2000 ndash 2001

Islam S Menopause 2009 16 77-83

Longitudinal observation of 80955 PM women from 2002 followed for 65 years hip fractures increased in those discontinuing HT versus those staying on HT

HR 155 (136-177) ndash began within 2 yrsKarim R Menopause 2011 18 1172-7

And What if You Stophellip

Mikkola TS Tuomikoski P Lyytinen H et al Increased cardiovascular mortality risk in women discontinuing

postmenopausal hormone therapy [published online ahead of print September 28 2015] J Clin Endocrinol Metab

MEN

WOMEN

Kindig D

Health

Affairs

32 451-8

2013

Simon 2015

13

So When Your Menopausal Patients Are

Get Mixed Signals About Hormone Therapyhellip

Conclusion

Compared with placebo the risks associated with HT in early menopausal women are statistically non-significant HT risks are rare and even more rare (lt11000 women per year of treatment) when initiated in women who are lt60 years of age andor lt10 years since menopause

The magnitude and type of risks associated with HT are less than or similar to other commonly used medications and therapies

HT reduces all-cause mortality CHD fractures and new onset diabetes mellitus and thus the benefits of HT far outweigh the risks

HT significantly reduced fractures in an unselected population of women (ie without osteoporosis or prior fractures) and is the most effective therapy for significantly reducing menopausal symptoms (vasomotor and vulvovaginal atrophy)

ldquoWe enter the world through

the brim of the pelvis and

frequently exit by the neck of

the femurrdquo

CA Newhall MD

Suggested Readingbull Pollycove R Naftolin F and Simon JA The evolutionary origin and significance of

Menopause Menopause 2011 Mar18(3)336-42

bull Lobo RA Where Are We 10 Years After the Womenrsquos Health Initiative J Clin Endocrinol

Metab 2013 May98(5)1771-80

bull Hodis HN Mack WJ The timing hypothesis and hormone replacement therapy a

paradigm shift in the primary prevention of coronary heart disease in women Part 1

comparison of therapeutic efficacy J Am Geriatr Soc 2013 Jun61(6)1005-10

bull Hodis HN Mack WJ The timing hypothesis and hormone replacement therapy a

paradigm shift in the primary prevention of coronary heart disease in women Part 2

comparative risks J Am Geriatr Soc 2013 Jun61(6)1011-1018

bull Gurney EP Nachtigall MJ Nachtigall LE Naftolin F The Womens Health Initiative trial

and related studies 10 years later A clinicians view J Steroid Biochem Mol Biol 2014

Jul1424-11

bull Simon JA What if the Womens Health Initiative had used transdermal estradiol and oral

progesterone instead Menopause 2014 Jul21(7)769-83

bull Sarrel P Portman D Lefebvre P et al Incremental direct and indirect costs of untreated

vasomotor symptoms Menopause 2015 Mar22(3)260-6

bull Manson JE Kaunitz AM Menopause Management mdash Getting Clinical Care Back on

Track N Engl J Med 2016 374(9) 803-806

Simon 2015

13

So When Your Menopausal Patients Are

Get Mixed Signals About Hormone Therapyhellip

Conclusion

Compared with placebo the risks associated with HT in early menopausal women are statistically non-significant HT risks are rare and even more rare (lt11000 women per year of treatment) when initiated in women who are lt60 years of age andor lt10 years since menopause

The magnitude and type of risks associated with HT are less than or similar to other commonly used medications and therapies

HT reduces all-cause mortality CHD fractures and new onset diabetes mellitus and thus the benefits of HT far outweigh the risks

HT significantly reduced fractures in an unselected population of women (ie without osteoporosis or prior fractures) and is the most effective therapy for significantly reducing menopausal symptoms (vasomotor and vulvovaginal atrophy)

ldquoWe enter the world through

the brim of the pelvis and

frequently exit by the neck of

the femurrdquo

CA Newhall MD

Suggested Readingbull Pollycove R Naftolin F and Simon JA The evolutionary origin and significance of

Menopause Menopause 2011 Mar18(3)336-42

bull Lobo RA Where Are We 10 Years After the Womenrsquos Health Initiative J Clin Endocrinol

Metab 2013 May98(5)1771-80

bull Hodis HN Mack WJ The timing hypothesis and hormone replacement therapy a

paradigm shift in the primary prevention of coronary heart disease in women Part 1

comparison of therapeutic efficacy J Am Geriatr Soc 2013 Jun61(6)1005-10

bull Hodis HN Mack WJ The timing hypothesis and hormone replacement therapy a

paradigm shift in the primary prevention of coronary heart disease in women Part 2

comparative risks J Am Geriatr Soc 2013 Jun61(6)1011-1018

bull Gurney EP Nachtigall MJ Nachtigall LE Naftolin F The Womens Health Initiative trial

and related studies 10 years later A clinicians view J Steroid Biochem Mol Biol 2014

Jul1424-11

bull Simon JA What if the Womens Health Initiative had used transdermal estradiol and oral

progesterone instead Menopause 2014 Jul21(7)769-83

bull Sarrel P Portman D Lefebvre P et al Incremental direct and indirect costs of untreated

vasomotor symptoms Menopause 2015 Mar22(3)260-6

bull Manson JE Kaunitz AM Menopause Management mdash Getting Clinical Care Back on

Track N Engl J Med 2016 374(9) 803-806