Hormone Replacement Therapyold.sfog.se/presentationer_sfogv08/nya rön om HRT.pdf · Postmenopausal...

Hormone Replacement TherapyFrom euphoria to panic and the need to find the equilibrium

1990s Euphoria 2002 - Panic

?Equilibrium

Nature Medicine, Vol 12;1, January 2006

Guidelines for HRTAmerican College of Physicians

1994

• All women should consider HRT

• Women with Coronary Artery Disease or are at risk for CAD are likely to benefit from hormone therapy

100

80

60

40

20

0-95 - 96 -97 - 98 - 99 2000 -01 -02 -03

WHI (EPT) 2002

106

YEAR

Prescriptions for all forms of HT in the US between 1995-2003 ( adapted from Hersh et al.,2004)

0

10000

20000

30000

40000

50000

60000

HT Prescriptions

SA Prescriptions

HT and Antidepressant HT and Antidepressant Prescription Patterns: A Prescription Patterns: A Reciprocal RelationshipReciprocal Relationship

Num

ber o

f Pre

scrip

tions

SA = serotonergic antidepressants.McIntyre RS, et al. CMAJ. 2005;172:57-9.

Jan 01

Mar 01

May 01

Jul 0

1Sep

01Nov 0

1Ja

n 02Mar

02May

02Ju

l 02

Sep 02

Nov 02

Jan 03

Mar 03

May 03

Jul 0

3Sep

03Nov 0

3

Period 1 Period 2

WHI Publication, July 17, 2002

Continuous Combined HRT Market SalesNordic region & country by country (.000€)

0

500

1000

1500

2000

2500

3000

Q3 2

002

Q1 2

003

Q3 2

003

Q1 2

004

Q3 2

004

Q1 2

005

Q3 2

005

Q1 2

006

,00

0 €

Finland Sweden Norway Denmark

y = 13,326x2 - 444,82x + 7044,1R2 = 0,9673

0

1 000

2 000

3 000

4 000

5 000

6 000

7 000

2002

Q 3

2003

Q 1

2003

Q 3

2004

Q 1

2004

Q 3

2005

Q 1

2005

Q 3

2006

Q 1

,00

0 €

Nordic Poly. (Nordic)

Source: IMS Health 2006, DLI-IMS 2006

Use of HT in Sweden and Norway

Average women1996: 30 – 50%2003: 15 – 25%Gynecologists1996: 80%2003: 70%

Moen et al, 2005Thunell, 2005

AFTER WHIAFTER WHI…………

Womens Health InitiativeWHI

Primary prevention

> 160 000 post menopausal women

50-79 years

Clinical trials and observational study

WHI

Primary prevention of major chronic illness: CVD, cancerand fractures

• Low fat diet• calcium + vitamin D• HRTvs placebo for 8-9 years

WHI

Primary prevention HRT28 000 women randomized

• ERT (CEE 0.625 mg/day)• cc HRT (CEE 0.625 mg/MPA 2.5 mg)• Placebo

WHI

NHLBI July 2002

cc HRT stopped early

Health risks exceed benefits after 5.2 years

ERT continues

WHI

Excess risk per 10 000 women years

CHD + 7Stroke + 8Breast cancer + 8Colon cancer - 6Hip fracture - 5

WHI

World Health Organization (WHO)Council for International

Organizations of Medical Sciences (CIOMS)

Classification of Frequency of Drug Reactions

Very common >1/10 (>10%)

Common (frequent) >1/100 and <1/10 (>1% and <10%)

Uncommon (infrequent) >1/1,000 and <1/100 (>0.1% and <1%)

Rare >1/10,000 and <1/1,000(0.01% and <0.1%)

Very rare <1/10,000 (<0.01%)

Object of WHI studyJacques Rossouw, National Heart Lung and Blood

Institute and principal WHI investigator said:

“Our main job at the time was to turn around the prevailing notion that hormones would be useful for long-term prevention of heart disease.

That was a worthy objective which we achieved”.

Wall Street Journal, July 9th, 2007

What is the cardioprotective role of HRTWhat is the cardioprotective role of HRT

is everything we is everything we ””knewknew”” wrong?wrong?

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

PremenopausalPostmenopausal

Incidence of Cardiovascular Disease: Relation to Menopause

Status

Inci

denc

e (p

er 1

,000

wom

en)

Age (years)Kannel W, et al. Ann Intern Med. 1976;85:447-52.

Observational Studies of CVD Risk and 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)

True primary prevention?Dose and regimenAge - 20% > 70 yearsBMI - 34% > 30 kg/m2

Effects of progestogen

WHI

HRT and cardioprotectionHRT and cardioprotection

•• timing of interventiontiming of intervention

•• concomitantconcomitant treatmenttreatment

•• dose and regimen dose and regimen e.g statinse.g statins

Hodis et alHodis et alCurr. Atheroscler. Rep. 2003;5:56Curr. Atheroscler. Rep. 2003;5:56

22nd Annual Therapeutic Options for Menopausal Health Conference

Wilmington, Delaware

CHALLENGES AND CHANGES IN POSITION STATEMENTS

-THE NAMS 2008 HT POSITION-

• Full 2008 position paper available online on NAMS Web site – www.menopause.org

• Published in July/August Menopause, 2008:15;584-603

• Published in Sept/Oct Menopause Management

• NAMS will update recommendations as more findings become available

First Global Summit on menopause-related issuesZürich, March 2008

HRT in the early menopause: scientific evidence andHRT in the early menopause: scientific evidence andcommon perceptionscommon perceptions

Aim: to bridge the gap between clinical factsand fears that are based on misperceptionsand misinformation in regard to hormone

replacement therapy, with a focus on women less than 60 years old.

(The full summary is available on www.imsociety.org)(The full summary is available on www.imsociety.org)

Global Summit

• Bullet points• Evidence grade:A = RCTB = case-control/observational studies

Cardiovascular system (1)

PerceptionHRT increases the risk of coronary heart disease (CHD) throughout the whole postmenopausal period.

EvidenceHRT in women aged 50–59 years does not increase CHD risk in healthy women and may even decrease the risk in this age group. [A]

Rossouw J. JAMA 2007;297:1465

0 1.0

<10

10-19

>20

Hazard Ratio (95% Confidence Interval)0.5

Years SinceMenopause

0.88

1.23

1.66

1.5 2.0 2.5

Effect of HT on CHD: Timing of Initiation

Rossouw JE, JAMA 2007;297:1465-1477.

WHI-E+P

P for trend=0.05

Absolute Risk per 10,000 Women per Year of HT Use

<10

10-19

>20

0.48

0.96

1.12

<10

10-19

>20

0.76

1.10

1.28

P for trend=0.02

WHI-E

WHI-Combined

-4

7

30

-14

-1

7

-6

4

16

P for trend=0.15

HT and CHD: the role of time since menopause

Nurses’ Health Study

Near menopauseRR (95% CI)

10yrs post menopauseRR (95% CI)

Estrogen 0.66 (0.54-0.80) 0.87 (0.69-1.10)

Estrogen + Progestogen

0.72 (0.56-0.92) 0.90 (0.62-1.29)

“These data support the possibility that timing of HT initiation in relation to menopause or to age might influence coronary risk.”

Grodstein F, Manson JE, Stampfer MJ. J Women’s Health 2006; 15: 35-44

Postmenopausal hormone therapy and risk of cardiovascular disease by age and years

since menopause

Dr Jacques Rossouw said:• “I understand some people are going to

say we’ve reversed course”• “What’s important about the analysis is

that it shows there may be some credence to the notion that there’s a ‘window of opportunity’ when hormone use is reasonably safe for younger women”.

Rossouw JE, Prentice RL, Manson J E. et al. JAMA 2007; 297: 1465-77

HERS: diabetes reduced by 35%HERS: diabetes reduced by 35%Postmenopausal women with CHDPostmenopausal women with CHD

n= 2763;age <80; follown= 2763;age <80; follow--up 4.1 yearsup 4.1 years

Incidence of diabetesIncidence of diabetes RH CIRH CI

CEE/MPA 6.2%CEE/MPA 6.2% 0.650.65 0.480.48--0.890.89

Placebo 9.5%Placebo 9.5%

Kanaya et alKanaya et alAnn Intern Med 2003;138:1Ann Intern Med 2003;138:1----99

HT & Diabetes MellitusHT & Diabetes Mellitus

•• HT reduces new DM onsetHT reduces new DM onset

•• Inadequate evidence to recommend HT for sole or Inadequate evidence to recommend HT for sole or primary indication for DM prevention in periprimary indication for DM prevention in peri-- or or postmenopausal womenpostmenopausal women

•• Transdermal ET may have advantages over oral Transdermal ET may have advantages over oral route in women with DMroute in women with DM

NAMS position statement. Menopause 2008:15;584-603.NAMS position statement. Menopause 2008:15;584-603.

HRT and metabolic syndromeHRT and metabolic syndrome

Salpeter SR et alSalpeter SR et alDiabetes, Obesity and MetabolismDiabetes, Obesity and Metabolism2006;8:5382006;8:538

mean changemean change 95% CI95% CI

abdominal obesityabdominal obesity --6.8%6.8% --11.8 11.8 −− --1.9%1.9%

insulin resistanceinsulin resistance --12.9%12.9% --17.117.1−− --8.6%8.6%

new onset diabetesnew onset diabetes RRRR0.70.7 0.6 0.6 -- 0.90.9

Pooled data from 107 RCTsPooled data from 107 RCTs33 315 women33 315 women

mean duration 1.5 yearsmean duration 1.5 years

HRT and CHDHRT and CHD

Salpeter SR et alSalpeter SR et alJ Gen Intern Med, 2006;21:363J Gen Intern Med, 2006;21:363

OROR 95% CI95% CI

< 60 years< 60 years 0.680.68 0.48 0.48 –– 0.960.96

> 60 years> 60 years 1.031.03 0.91 0.91 –– 1.161.16

Pooled data from 23 RCTsPooled data from 23 RCTs39 049 women39 049 women

mean duration 4.9 mean duration 4.9 ±± 17 years17 years

HT & Coronary Heart DiseaseHT & Coronary Heart Disease

•• HT may reduce CHD risk when initiated in younger and more HT may reduce CHD risk when initiated in younger and more recently postmenopausal womenrecently postmenopausal women

•• Longer HT duration associated with reduced CHD risk and Longer HT duration associated with reduced CHD risk and mortalitymortality

•• Some evidence of lower CHD risk in women with HT Some evidence of lower CHD risk in women with HT ≥≥5 y5 y

•• ShortShort--term HT may increase CHD risk in women farther from term HT may increase CHD risk in women farther from menopause at time of initiationmenopause at time of initiation

•• LongLong--term HT associated with less accumulation of coronary term HT associated with less accumulation of coronary artery calciumartery calcium

•• HT currently not recommended as sole or primary indication HT currently not recommended as sole or primary indication for coronary protection in women of any agefor coronary protection in women of any age


Abs

olut

e R

isk

-30

-20

-10

0

10

20

30

40

50

CHD Stroke VTE BreastCancer

TotalDeath

GlobalIndex

50-5960-6970-79

WHI-E: Number of Events per 10,000 Women per Year of CEE Therapy

Writing Group for the Women's Health Initiative Investigators. JAMA 2004;291:1701-1712.Rossouw, et al. JAMA 2007;297:1465-1477.

WHI: HT use and mortality by WHI: HT use and mortality by age at baselineage at baseline

AgeAge HRHR 95% CI95% CI

50 50 –– 5959 0.700.70 0.51 0.51 –– 0.960.96

60 60 –– 6969 1.051.05 0.87 0.87 –– 1.261.26

70 70 –– 7979 1.141.14 0.94 0.94 –– 1.371.37

Rossouw J et al, Rossouw J et al, JAMA 2007;297:1465JAMA 2007;297:1465


PerceptionHRT causes an increase in coronary events in the first 1–2 years in all women.

EvidenceEarly harm (more coronary events during the first 2 years of HRT) was not observed in the early postmenopausal period. The number of CHD events decreased with duration of HRT in both WHI clinical trials. [A]

Lobo R. Arch Intern Med 2004;164:482

Cardiovascular system (3)PerceptionStroke risk is substantially increased in women receiving HRT.

EvidenceIt is unclear at present whether there is a statistical increase in ischemic stroke with standard HRT in healthy women aged 50–59. The WHI data showed no statistically significant increase inrisk; nevertheless, even if statistically increased, as found in the Nurses’ Health Study, the low prevalence of this occurrence in this age group makes the attributable risk extremely small. [A,B]

Hendrix SL. Circulation 2006;113:2425Grodstein F. Arch Intern Med 2008;168:861

Absolute Risk of Stroke inWHI Trials

No. of Additional Confidence Interval Cases of Stroke per

Nominal Adjusted 10,000 Women per HR 95% CI 95% CI Year of Therapy

CEE-MPA 1.31 1.03-1.681 0.93-1.842 8

CEE 1.33 1.05-1.681 0.97-1.993 11

1Rossouw J, et al. JAMA 2007;297:1465-1477.2Wassertheil-Smoller S, et al. JAMA 2003;289:2673-2684.3Writing Group for the Women's Health Initiative Investigators. JAMA 2004;291:1701-1712.

Average age = 64; Average time since menopause >10 years

Absolute Risk of Stroke According to Years Since Menopause (WHI-EP Trial) and Age

(WHI-E Trial) when RandomizedAbsolute Risk

Number of Strokes per 10,000Women per Year

No. of Additional Cases of Stroke per 10,000 Women

per Year of Therapy

CEE+MPA(n=8506)

Placebo(n=8102)

Years Since1

Menopause

<5 7 10 35 to <10 11 17 610 to 15 17 27 10>15 42 48 6

Age2

50-59 17 15 -260-69 31 51 2070-79 59 76 16

1Wassertheil-Smoller S, et al. JAMA 2003;289:2673-2684.2Rossouw J, et al. JAMA 2007;297:1465-1477.

CEE(n=5310)

Placebo(n=5429)

HT & StrokeHT & Stroke

•• Both ET and EPT appear to increase ischemic Both ET and EPT appear to increase ischemic stroke risk and have no effect on hemorrhagic stroke risk and have no effect on hemorrhagic stroke risk in postmenopausal womenstroke risk in postmenopausal women

•• HT cannot be recommended for primary or HT cannot be recommended for primary or secondary prevention of strokesecondary prevention of stroke



PerceptionThe risk of venous thromboembolism is increased during HRT.

EvidenceThe risk of venous thrombosis in the early menopause is approximately two-fold higher with standard doses of oral HRT, but is a rare event in that the background prevalence is extremely low in a healthy woman under 60 years of age. [A]The risk of venous thrombosis is possibly less with transdermal, compared with oral estrogen therapy. [B]

Cushman M. JAMA 2004;292:1573Canonico M. Circulation 2007;115:840

HRT and risk of VTE; systematic review and meta-analysis

Pooled O R Pooled 95% CI

Observational studies

Oral oestrogen2.5 1.9-3.4

Transdermal 1.2 0.9-1.7

Randomised controlled trials

Oral oestrogen2.1 1.4-3.1

Canonico M, Plu-Bureau G, Lowe G, Scarabin P-Y. BMJ 2008; 336: 1227-31

HT & Venous ThromboembolismHT & Venous Thromboembolism

•• Oral HT increases VTE risk in postmenopausal Oral HT increases VTE risk in postmenopausal women women

•• VTE risk emerges soon (1VTE risk emerges soon (1--2 y) after HT initiation 2 y) after HT initiation and decreases over timeand decreases over time

•• Lower VTE risk with either EPT or ET in women Lower VTE risk with either EPT or ET in women <60 y<60 y

•• Lower VTE risk with transdermal than with oral ETLower VTE risk with transdermal than with oral ET

•• Lower HT doses may be safer than higher dosesLower HT doses may be safer than higher doses

•• Risks fall into the Risks fall into the ““rarerare”” categorycategory


Bone (1)PerceptionHRT should not be used for bone protection because ofits unfavorable safety profile. Official recommendationsby health authorities (EMEA, FDA) limit the use of HRTto a second-line alternative. HRT could only be consideredwhen other medications failed, were contraindicated or nottolerated, or in the very symptomatic woman.

EvidenceFor the age group 50–59, HRT is safe and cost-effective. Overall, HRT is effective in the prevention of all osteoporosis-related fractures, even in patients at low risk of fracture. [A]

Rossouw J. JAMA 2007:297:1465; Cauley JA. JAMA 2003;290:1729Jackson RD. J Bone Min Res 2006;21:817

Bone (2)

PerceptionHRT is not as effective in reducing fracture risk as other products (bisphosphonates, etc.).

EvidenceAlthough no head-to-head studies have compared HRT to bisphosphonates in terms of fracture reduction, there is no evidence to suggest that bisphosphonates or any other antiresorptive therapy are superior to HRT.

Fracture risk in the WHI studyHazard ratio

Estrogen + progestin hormone therapy

Hazard ratioEstrogen hormone therapy

Hip 0.67 (0.47–0.96)*

0.61 (0.41–0.91)*

Vertebral 0.65 (0.46–

0.92)*0.62 (0.42–0.93)*

Total 0.76 (0.69–

0.83)*0.70 (0.63–0.79)*

* significantAdapted from JAMA 2003;290:1729and JAMA 2004;291:1701

HT & OsteoporosisHT & Osteoporosis

•• HT proven to reduce postmenopausal osteoporotic HT proven to reduce postmenopausal osteoporotic fracturesfractures

•• Many systemic ETMany systemic ET--containing products approved for containing products approved for prevention of postmenopausal osteoporosis through prevention of postmenopausal osteoporosis through longlong--term treatment term treatment

•• Extended use of HT is option for women with low bone Extended use of HT is option for women with low bone mass, regardless of menopause symptoms, when mass, regardless of menopause symptoms, when alternate therapies not appropriate alternate therapies not appropriate


Cognition (1)

PerceptionMenopause transition is associated with cognitive decline.

EvidenceThere is no evidence of substantial cognitive decline across themenopausal transition. [A] However, many women experience cognitive difficulties in association with vasomotor symptoms, sleep disturbances and mood changes. [B]

Meyer PM. Neurology 2003;61:801; Maki PM. Menopause 2008 (in press)Woods NF. J Womens Health 2007;16:667

Cognition (2)PerceptionHRT increases the risk of cognitive/memory impairment and dementia at any age.

EvidenceNo cognitive benefit was found among women initiating HRT late in the postmenopausal period (after age 65). [A]Observational studies show a decreased risk of Alzheimer’s disease in hormone users and typically involve women who initiated estrogen therapy early in the menopausal transition. [B] Cognitive benefits from estrogen therapy appear to depend on age at initiation. [B]

Espeland MA. JAMA 2004;291:2959; Tang M-X. Lancet 1996;348:429Bager YZ. Menopause 2005;12:12

Cognition (3)

PerceptionProgestogens counteract estrogen effects in the brain.

EvidenceLimited data exist on the effect of progestogen added to estrogen in the early postmenopause period.

Misperception

HRT risks outweigh benefits

Total Mortality Associated with HRT in Younger and Older Women:

Meta-analysis of 30 Randomized Controlled Trials

HRT vs. Control OR (95% CI)All ages 0.98 (0.87-1.18)

>60 years old; Mean age = 66 years 1.03 (0.91-1.16)

<60 years old; Mean age = 54 years 0.61 (0.39-0.95)

Salpeter S, et al. J Gen Intern Med 2004;19:791-804.

Misperception

HRT risks are large in magnitude

Misperception

HRT risks/benefits are greater/less than other commonly used therapies

in the primary prevention of CHD

Primary Prevention of CHD withLipid-Lowering Therapy in Women

Primary6 RCTs11,435 women

Outcome RR (95% CI)

CHD events 0.89 (0.69-1.09)Non-fatal MI 0.61 (0.22-1.68)CHD mortality 1.07 (0.47-2.40)Total mortality 0.95 (0.62-1.46)

Secondary8 RCTs8,272 women

RR (95% CI)

0.80 (0.71-0.91)0.73 (0.59-0.90)0.74 (0.55-1.00)1.00 (0.77-1.29)

Walsh JME, et al. JAMA 2004;21:363-366.

Breast Cancer in Randomized Controlled Trials of Hormone and Statin Therapy

TherapyPlacebo Study

-21.005 (0.53)5 (0.55)

80.94-1.531.20199 (0.41)150 (0.33)CEE+MPA

WHI-EP120.77-2.191.3032 (0.57)25 (0.45)HERS

95% CI

No. of Patients (Annualized %)

No. Additional Breast Cancer

Cases per 10,000 Women per Year of

TherapyRelative

Risk

-80.65-1.040.82129 (0.34)161 (0.42)CEE alone

WHI-E

0.30-3.5017B-E2 alone

WEST

150.78-3.491.6518 (0.38)11 (0.23)STATIN

PROSPER150.62-3.361.4413 (0.50)9 (0.35)AFCAPS50.46-4.521.447 (0.17)5 (0.11)4S-10 y f/u

772.48-59.8012.1712 (0.82)1 (0.07)CARE00.42-2.421.0010 (0.22)10 (0.22)LIPID

-20.58-1.480.9334 (0.28)37 (0.30)ALLHAT-LLT-100.49-1.130.7538 (0.30)51 (0.40)HPS

Primary Prevention of CHD with HRT in Clinical Perspective

7(0.79-2.26)1.3381 (0.30)64 (0.23)Statins meta1

8(0.94-1.53)*1.20199 (0.41)150 (0.33)WHI-EP3

-8(0.65-1.04)0.82129 (0.34)161 (0.42)WHI-E4**

95% CI

No. of Patients (Annualized %)

No. Additional Breast Cancer

Cases per 10,000 Women per Year of

Stain UseHazard RatioStatinPlacebo Study

1Dale KM, et al. JAMA 2006;295:74-80.2Stefanos, et al. J Clin Oncol 2005;23:8606-8612.3Anderson G, et al. Maturitas 2006;55:103-115.4Stefanick ML, et al. JAMA 2006;295:1647-1657.

2(0.81-1.33)1.04132 (0.31)124 (0.29)Statins meta2

*Adjusted for age, race/ethnicity, BMI, physical activity, smoking, alcohol use, parity, OC use, family history of breast cancer and fractures, mammography use and vasomotor symptoms**Adherence adjusted = 0.67 (0.47-0.97)**Ductal carcinoma = 0.71 (0.52-0.99)

Primary Prevention of CHD with HRT in Clinical Perspective

*Women <60 years old and/or <10 years since menopause when randomized

1Salpeter S, et al. J Gen Intern Med 2004;19:791-804.2Salpeter S, et al. J Gen Intern Med 2006;21:363-366.3Walsh JME, et al. JAMA 2004;21:363-366.4Ridker PM, et al. N Engl J Med 2005;352:1293-1304.

Hormone LipidOutcome Therapy1,2* Lowering3 Aspirin4

CHD 0.68 (0.48-0.96) 0.89 (0.69-1.09) 0.91 (0.80-1.03)

Total Mortality 0.61 (0.39-0.95) 0.95 (0.62-1.46) 0.95 (0.85-1.06)

Breast- a target for reproductive hormones

Basic knowledge on hormonal effects is very poor

Bröstcancerrisk

RR• p-piller 1.24 Lancet 1996;347:1713

• HRT 1.24 JAMA 2003;209:3243

• grapefrukt 1.30 Br J Cancer 2007;97:440

HRT and Breast Cancer51 studies > 160,000 women

Cumulative incidence age 50-70 per 1000 women:

Never user 45HRT – 5 years 47(+ 2)HRT – 10 years 51(+ 6)HRT – 15 years 57(+12)

• No excess risk 5 years after HRT• BC less clinically advanced• More favourable prognosis

Lancet 1997; 350:1047-59

Incidence / 100.000

25 35 45 55 65 75

10

100

Age

Normal

Oophorectomy at age 30

Age-incidence curves of breast cancer in women with natural menopause and in women with bilateral ovariectomy at 30 years of age. Adapted from Spicer & Pike, 1993

2.5 cm

1 mm

1012

1010

108

106

104

1

1 2 3 4 5 6 7 8 9 10 11 12 13 14 Years

Premammographic Preclinical Clinical

The mammographic window

1 cm Breast tumor

Cell number

Wertheimer et alJAMA 1986;255:1311

69

Chlebowski et al,JAMA 2003; 289: 3243–53

The WHI Steering Committee, JAMA 2004; 291:1701-12

WomenWomen’’s Health Initiatives Health Initiative

placebo

CEE + MPA

placeboCEE + MPAplacebo

CEE

EE--onlyonly EPTEPT

WHI: prior HT use and breast WHI: prior HT use and breast cancercancer

Anderson GL et alAnderson GL et alMaturitas 2006;55:103Maturitas 2006;55:103

E+PE+P PlaceboPlacebo HRHR 95% CI95% CINo prior HTNo prior HT

incidenceincidence 141/6277141/6277 121/6020121/6020

annual %annual % 0.400.40 0.360.36 1.021.02 0.770.77--1.361.36

Prior HTPrior HT

incidenceincidence 58/222958/2229 29/208229/2082

annual %annual % 0.460.46 0.250.25 1.961.96 1.171.17--3.273.27

HRHR 95% CI95% CITotal materialTotal material 0.800.80 (0.62 (0.62 –– 1.04)1.04)Ductal carcinomaDuctal carcinoma 0.710.71 (0.52 (0.52 –– 0.99)0.99)

Localized diseaseLocalized disease 0.690.69 (0.51 (0.51 –– 0.95)0.95)

Adherence to Adherence to treatmenttreatment

0.670.67 (0.47 (0.47 –– 0.97)0.97)

Stefanick et al.Stefanick et al.JAMA 2006;295:1647JAMA 2006;295:1647

WHI WHI -- Estrogen aloneEstrogen alone

Breast cancerBreast cancer

ERT vs HRT

Progestin related side effects

HRT and overall cancer riskHRT and overall cancer risk

population based cohortpopulation based cohort29 508 women29 508 women

cancer at age 75cancer at age 7511451145

SIRSIR 95% CI95% CIEver use of HRT 1.07Ever use of HRT 1.07 0.96 0.96 –– 1.191.19

No risk increaseNo risk increase

Olsson et alOlsson et al

Br J Cancer 2001;85:674Br J Cancer 2001;85:674

HRT and smokingHRT and smoking--associated cancerassociated cancer

SIR/ORSIR/OR 95% CI95% CILong term HRT (oral, Long term HRT (oral, larynx, lung, cervix larynx, lung, cervix and bladder)and bladder)

0.240.24 0.08 0.08 –– 0.760.76

Olsson et alOlsson et alObstet Gynecol 2003;102:565Obstet Gynecol 2003;102:565

Long term HRT Long term HRT (lung)(lung)

0.590.59 0.37 0.37 –– 0.930.93

Kreuzer et alKreuzer et alInt J Epidemiol 2003;32:263Int J Epidemiol 2003;32:263

HRT use (lung)HRT use (lung) 0.660.66 0.51 0.51 –– 0.890.89

Schabath et alSchabath et alClin Cancer Res 2004;10:113Clin Cancer Res 2004;10:113

HRT och cancer

ökad risk minskad riskbröstcancer coloncancer

livmodercancerovarialcancer ?? lungcancer ??

blåscancer ??

Ingen förändring av dentotala risken

Östrogenbehandling är inte ett enhetligt begrepp

• Olika östrogener i olika doser med och utan gestagentillägg

• Oral eller parenteral tillförsel• Systemterapi eller lokal lågdosbehandling

Breast (1)

PerceptionAll types of HRT cause an increased risk of breastcancer within a short duration of use.

EvidenceAfter 5 years’ use of combined estrogen and progestogen, the WHI cohort showed a small increase in risk of breast cancer of about eight extra cases per 10,000 women per year. Risk was not increased in first-time hormone users. [A]

Chlebowski RT. JAMA 2003;289:3243Stefanic ML. JAMA 2006;295:1647

Breast (1) cont.

PerceptionAll types of HRT cause an increased risk of breastcancer within a short duration of use.EvidenceIn the WHI estrogen-only arm, there was no increase in breast cancer risk for up to 7 years. However, the risk of invasive breast cancer was significantly lower in first-time users of estrogen. [A] In observational studies, a small increase in risk during estrogen-alone therapy was recorded only after long-term use. [B]

Anderson GL. JAMA 2004;291:1701; Stefanic ML. JAMA 2006;295:1647Chen WY. Arch Intern Med 2006;166:1027

HT & Breast CancerHT & Breast Cancer

•• Breast cancer risk increases with EPT use beyond 3Breast cancer risk increases with EPT use beyond 3--5 y5 y

•• Increased absolute risk of EPT in WHI is viewed as Increased absolute risk of EPT in WHI is viewed as ““rarerare”” (4(4--6 additional cases/10,000 women/y of EPT for 6 additional cases/10,000 women/y of EPT for ≥≥5 y)5 y)

•• Unclear whether EPT risk differs between continuous and Unclear whether EPT risk differs between continuous and sequential progestogen usesequential progestogen use

•• WHI ET trial showed no increased risk after 7.1 y (6 fewer WHI ET trial showed no increased risk after 7.1 y (6 fewer cases/10,000 women/y of ET use; not statistically significant)cases/10,000 women/y of ET use; not statistically significant)

•• ET for <5 y has little impact on breast cancer riskET for <5 y has little impact on breast cancer risk


HT & Breast Cancer (contHT & Breast Cancer (cont’’d)d)

•• EPT and, to a lesser extent, ET, increase breast EPT and, to a lesser extent, ET, increase breast cell proliferation, breast pain, and mammographic cell proliferation, breast pain, and mammographic densitydensity

•• EPT may impede diagnostic interpretation of EPT may impede diagnostic interpretation of mammogramsmammograms

•• Whether to use HT when history of breast cancer is Whether to use HT when history of breast cancer is unresolved (limited epidemiologic evidence mixed; unresolved (limited epidemiologic evidence mixed; no completed longno completed long--term RCTs)term RCTs)


2007;356:1670-1674

Withdrawal responseWithdrawal response

••Tumor response after withdrawal of Tumor response after withdrawal of endocrine therapy has been reported for:endocrine therapy has been reported for:•• estrogen, androgen, progestogen, estrogen, androgen, progestogen, tamoxifen and HRTtamoxifen and HRT••Stimulation of apotosis?Stimulation of apotosis?••Duration of WR uncertainDuration of WR uncertain

Prasad et al, Cancer 2003;98:2539Prasad et al, Cancer 2003;98:2539Howell et al, Ann. Oncol 1992;3:611Howell et al, Ann. Oncol 1992;3:611

Summary Summary

•• The HT benefitThe HT benefit--risk ratio continually changes with womanrisk ratio continually changes with woman’’s s age and menopauseage and menopause--related symptomsrelated symptoms

•• Ratio is more favorable close to menopause, but decreases Ratio is more favorable close to menopause, but decreases with aging and time since menopause in previously untreated with aging and time since menopause in previously untreated womenwomen

•• Recent data support HT initiation around the time of Recent data support HT initiation around the time of menopause to:menopause to:

---- Treat menopauseTreat menopause--related symptoms and/orrelated symptoms and/or

---- Treat or reduce the risk of certain disorders (eg, Treat or reduce the risk of certain disorders (eg, osteoporosis or fractures) in select postmenopausal women osteoporosis or fractures) in select postmenopausal women

•• HT use should be consistent with treatment goals, benefits, HT use should be consistent with treatment goals, benefits, and risks for the individual womanand risks for the individual woman


HT & Total MortalityHT & Total Mortality

•• HT may reduce total mortality when initiated soon HT may reduce total mortality when initiated soon after menopauseafter menopause

•• Both ET and EPT may reduce total mortality by Both ET and EPT may reduce total mortality by 30% when initiated in women <60 y30% when initiated in women <60 y

•• HT not associated with mortality reduction among HT not associated with mortality reduction among women who initiate HT at women who initiate HT at ≥≥60 y60 y


HT Duration of UseHT Duration of Use

•• No clear indication that longer HT duration No clear indication that longer HT duration improves or worsens the benefitimproves or worsens the benefit--risk ratio risk ratio

•• HT effects on longHT effects on long--term risks have not been studied term risks have not been studied in perimenopausal women in perimenopausal women

•• Thus, findings from RCTs of postmenopausal Thus, findings from RCTs of postmenopausal women should be extrapolated with caution for women should be extrapolated with caution for younger womenyounger women


Daily Mirror

Sky News

Daily MailGuardian

The Times

The Telegraph

BBC News

Reuters

HRT 2008HRT 2008

Standard doses IndividualisationStandard doses Individualisation Selective treatmentSelective treatment

One for allOne for all doses, age doses, age bisphosphonatesbisphosphonates

All for one body composAll for one body compositionition SERM, SSRISERM, SSRI

tibolone/androgenstibolone/androgens

Alternatives to progestogensAlternatives to progestogens

Symptomatic treatment Symptomatic treatment Long term Long term preventionprevention

Not controversial Not controversial for whom, for whatfor whom, for what

BEHANDLING AV BEHANDLING AV PERIMENOPAUSALA SYMPTOMPERIMENOPAUSALA SYMPTOM

•• Effektiv och ofta fEffektiv och ofta föörsummadrsummad

•• Medelpotenta Medelpotenta ööstrogener, lstrogener, läägsta gsta effektiva dos, gestagentilleffektiva dos, gestagentilläägggg

•• AvgrAvgräänsad behandling cirka 5 nsad behandling cirka 5 åårr

•• Inga fInga föörvrvääntade riskerntade risker

BEHANDLING AV UROGENITALA BEHANDLING AV UROGENITALA ATROFISYMPTOMATROFISYMPTOM

•• Effektiv och mycket ofta fEffektiv och mycket ofta föörsummadrsummad

•• LLååg g ööstrogendos, lokalt strogendos, lokalt -- peroraltperoralt

•• Ofta (livs)lOfta (livs)låång behandlingng behandling

•• Inga fInga föörvrvääntade riskerntade risker

GENERELL GENERELL LLÅÅNGTIDSPROFYLAXNGTIDSPROFYLAX

•• Sannolikt effektivSannolikt effektiv--osteoporos; hjosteoporos; hjäärtrt--kkäärlsjukdom?rlsjukdom?

•• KrKrääver medelpotenta ver medelpotenta ööstrogener under strogener under llåång tidng tid

•• ÄÄnnu osnnu osääker balans nytta ker balans nytta -- riskrisk•• Kan Kan äännu ej rekommenderasnnu ej rekommenderas•• Forskning om urval och riskgrupper pForskning om urval och riskgrupper pååggåårr

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