Hormone therapy (HT) Epidemiological aspects jvind Lidegaard - - PowerPoint PPT Presentation

Hormone therapy (HT) Epidemiological aspects

Øjvind Lidegaard

Professor, DMSc

Gynaecological Clinic 4232 Rigshospitalet Copenhagen University

www.lidegaard.dk/slides

Hormone therapy; an update

• Hormone use
• HT - breast cancer
• HT - endometrial cancer
• HT - ovarian cancer
• HT - colo-rectal cancer
• HT - heart and circulation
• HT - death
• Conclusion

HT sale DK 2002. DDD/1,000 per day

50 100 150 200 250 15-39 40-44 45-49 50-54 55-59 60-64 65-69 70+ Local Mirena Comb cont Comb cycl Progestagen Oestrogen

Danish Sex Hormone Register Study (DaHORS).

www.dachre.dk

HT sale DK 2004. DDD/1,000 per day

50 100 150 200 250 15-39 40-44 45-49 50-54 55-59 60-64 65-69 70+ Local Mirena Comb cont Comb cycl Progestagen Oestrogen

www.dachre.dk

Danish Sex Hormone Register Study (DaHORS).

Hormone therapy; an update

• Hormone use
• HT - breast cancer
• HT - endometrial cancer
• HT - ovarian cancer
• HT - colo-rectal cancer
• HT - heart and circulation
• HT - death
• Conclusion

HT and cancer

Axes of significance:

• Duration of therapy
• Regimen (ET, EPT, tibolone)
• Long cycle, cyclic, cont. combined
• Route: Oral, dermal, vaginal, IUD
• Estrogen dose
• Progestagen type
• Progestagen dose

Breast cancer incidence rate by age

2 3 22 50 127 189 244 271 352 368 326 338 324 342

50 100 150 200 250 300 350 400

< 1 5 1 5

• 1

9 2

• 2

4 2 5

• 2

9 3

• 3

4 3 5

• 3

9 4

• 4

4 4 5

• 4

9 5

• 5

4 5 5

• 5

9 6

• 6

4 6 5

• 6

9 7

• 7

4 7 5

• 7

9 8

• 8

4 8 5 +

Total: 4,000 per year Lifetime risk: 10%

Health statistics, National Board of Health, DK 2003

Incidence per 100,000 80% 20%

BC incidence rate in Norway 2005

1 6 21 55 96 179 226 270 305 332 212 252 323 272

50 100 150 200 250 300 350 400

< 1 5 1 5

• 1

9 2

• 2

4 2 5

• 2

9 3

• 3

4 3 5

• 3

9 4

• 4

4 4 5

• 4

9 5

• 5

4 5 5

• 5

9 6

• 6

4 6 5

• 6

9 7

• 7

4 7 5

• 7

9 8

• 8

4 8 5 +

Cancer Registry, Norway

Incidence per 100,000

BC incidence rate in DK 1945-2000

61 62 63 66 72 78 86 92 98 105 112 119

50 60 70 80 90 100 110 120

45 50 55 60 65 70 75 80 85 90 95 20

Oksbjerg S. Ugeskr Læger 1997; 159: 7134-40.

Incidence per 100,000 age standardised

Li/07

Body mass index and risk of breast cancer

1 1,09 1,02 0,93 0,87 1 1,04 1,14 1,21 1,41

0,8 1 1,2 1,4 1,6

13-20.2 20.2-21.7 21.8-23.4 23.5-26.5 26.6-54

Cases: 6548 Controls: 9057

Trentham-Dietz. Am J Epidemiol 1997; 145: 1011-9. Confounder control: parity, menarche, family histpry of BC, age at first full-term pregn, alcohol consumption, education

Physical activity and breast cancer

Cohort study of 25,624 women. Follow up: 13.7 years

1 0,93 0,63 1 0,84 0,74 0,48

0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1 1,1 Little Moderate Regular Heavy

Relative risk (95% CI) Adjusted for age, BMI, residence, number of births Work Leisure

Thune I, N Engl J Med 1997; 336: 1269-75

Fruit and vegetables: influence on pre-menopausal BC

0,3 0,4 0,5 0,6 0,7 0,8 0,9 1 1,1

<16 16-19 20-24 >24 Risk of premenopausal BC (95% CL)

Confounder control: Age at first birth, menarche, education, family BC, BMI, and total caloric intake Cases: 297 Controls: 311

• Freundenheim. J Natl Canc Inst 1996; 88: 340-8.

g/day

Alcohol intake and risk of breast cancer

drinks per day

1 1,1 1,2 1,3 1,4 1,5

1 2 3 4 Risk of BC (95% CL)

• Longnecker. Canc Causes and Control 1994; 5: 73-82

Beral V et al. Lancet 2002; 87: 234-45

13%/drink 7.1%/drink

Family disposition and BC

1 1,8 2,9 3,9

1 1,5 2 2,5 3 3,5 4

1 2 3+ Risk of BC (95% CL)

Collaborative group, Lancet 2001; 358: 1389-99

Age at first birth and risk of BC

1 1,1 1,5 1,7

1 1,2 1,4 1,6 1,8

<20 20-24 25-29 30+ Risk of BC (95% CL)

Case-control study Norway 373 cases 1,150 controls Vatten LJ. Br J Cancer 2002, 86: 89-91

Age at first birth DK 1965-2006

Increase: 1 year/5 years

22,7 23,7 24 24,6 25,5 26,4 27,5 28,1 30

22 23 24 25 26 27 28 29 30 1965 1970 1975 1980 1985 1990 1995 2000 2006

Childless at 49 years 1995: 7.9% Childless at 49 years 2000: 12.1% Childless at 49 years 2005: 12.7%

Online statistics: www.dst.dk

Age at first birth DK and No

Increase: 1 year/5 years

22,7 23,7 24 24,6 25,5 26,4 27,5 28,1 22,5 22,8 23,6 24,4 25 26 26,9 27,5 30

22 23 24 25 26 27 28 29 30 1965 1970 1975 1980 1985 1990 1995 2000 2006

Online statistics: www.dst.dk and www.fhi.no

Breast cancer and birth weight

1 1,6 2,4 3,5 1 0,75 1 0,9 1 1,2 1,24 1,6 1,8

1 2 3

<2½ 2½-3 3-3½ 3½-4 >4 <3 3-3½ 3½-4 >4

Lancet 1996; 348: 542-6. BMJ 2003; 326: 248-53.

Nurses Health Study 582 nurses with BC 1,569 without Cohort study 5358 women Sweden

Breastfeeding, parity and breast cancer

1 0,94 0,86 0,84 0,73

0,97 0,93 0,83 0,73 0,64

0,6 0,7 0,8 0,9 1

1 2 3 4 >4

Relative risk (95% CI) Never breastfeed Ever breastfeed Number of births

Collaborative group. Lancet 2002; 360: 187-95.

Can we explain the increase?

Yes:

• Increase in age at first birth 21→29 years
• Higher birth weight
• Less physical activity
• Fewer children per woman
• Increase in daily alcohol consumption
• Dramatic increase in BMI

These factors fully explain the increase

Lidegaard & Kroman. Eur Clinics Obstet Gynaecol 2005; 1: 24-8

Breast cancer: Risk factors

Family breast cancer (RR 2) Night work (RR 1-1.5) Breast cancer Alcohol (RR 1.10/drink) Fibers (RR 0.5) Adiposity (RR 1.4) Physical activity (RR 0.5) HT Age at first birth 30 vs 20: (RR 1.5)

HT and breast cancer (BC) Metaanalysis from 1996

• Current HT increases the risk of breast

cancer by 10-30% (5-15 years)

• The risk was 16% higher for comb. HT.
• The risk increased with duration of use
• The risk faded out after cessation
• Women with BC and previous HT have a

better survival than BC patients without previous HT => no increased risk of death

Metaanalysis: 52,705 cases, 108,411 controls. Lancet 1997

HT and BC: Randomised studies

Risk after 5.2 and 6.8 years MPA+EE

1,26 1,27 0,5 1 1,5 2 2,5

WHI HERS

WHI study: Cohort: 8,506 EE+MPA, 8,102 placebo. Follow up: 5.2 yrs. Endpoints: 166 exposed, 124 non-exposed

Rossouw et al. JAMA 2002; 288: 321-33. Hulley et al. JAMA 2002; 288: 58-66

HERS: 5,100 women with AMI randomised for EE+ MPA 2,5mg. Follow up 6.8 years. Endpoints: 49 exposed, 39 non-exposed women with BC

WHI results

EPT ET 50-59

• Coronary heart disease

1.3 0.9 0.6

• Stroke

1.4 1.4 1.1

• Venous thromboembolism

2.1* 1.3 1.2

• Breast cancer

1.3 0.8 0.7

• Endometrial cancer

0.8 hysterect.

• Colorectal cancer

0.6 1.1 0.6

• Hip fracture

0.7 0.6 NA

• Vertebral fracture

0.7 0.6 NA

• All cause mortality

1.0 1.0 0.7

Rossouw et al. JAMA 2002; 288: 321-33.

Million women study

Design:

• A prospective cohort study

Cohort:

• Women invited with invitation to breast cancer
• screening. 75% accepted screening,

71% of screened (53% of all) accepted participation in the study.

• Age: 50-64 years at baseline
• Recruitment: May 1996 – March 2001

Follow up

• Incidence: Dec 2000 or 2001; 2.6 years
• Mortality: December 2002; 4.1 years

Lancet 2003; 362: 419-27

Risk in women currently on HT

1 1,66 1,01 1,04 1,01 0,9

0,7 0,8 0,9 1 1,1 1,2 1,3 1,4 1,5 1,6 1,7 1,8

Never use Current use All past use Last use <5 yrs Last use 5-9 yrs Last use 10+

Lancet 2003; 362: 419-27

Risk on different regimens

1 1,3 2 1,45 1,22

0,9 1,1 1,3 1,5 1,7 1,9 2,1

Never Est only Est + Prog Tibolone Death

Oestrogen only therapy

1 1,3 1,25 1,19 1,32 1,24 0,8 1 1,2 1,4 1,6 1,8 2 Never Oest only Estrad <1mg Estrad >1mg Oral Dermal

Oestrogen-progestagen therapy

Influence from different progestagens

1,6 1,5 2 1,8 1,6 2,4 2,1 2,2 2,1 2,4 1 1,4 1,8 2,2 2,6

MPA NETA Levo Seq. Cont. MPA NETA Levo Seq. Cont.

<5 years >5 years

Danish sex Hormone Register Study DaHoRS (1.8 mio women study)

Hormone therapy and breast cancer

Øjvind Lidegaard Ellen Løkkegaard Lisbeth Møller Carsten Agger Anne Helms Andreasen

DaHoRS: Principal study design

• A National cohort of women
• 15-69 years old per January 1, 1995
• Followed from January 1995 through 2002
• Exposures and outcomes from national

registers

• Assessing the influence of OC and HT on

the risk of cardiovascular diseases and cancer

• Details on www.dachre.dk

Danish Sex Hormone Register Study (DaHoRS): www.dachre.dk

Hormone therapy and breast cancer

• Cohort: Included women 50-69:

785,397

• Exposed women (current+prev): 234,955
• Control women (never users):

550,442

• Women currently on HT with BC:

3,010 2.5

• Women previously on HT w BC:

1,957 1.7

• Women never on HT with BC:

7,864 1.4

• Included with BC:

12,831

Danish Sex Hormone Register Study (DaHoRS): www. dachre.dk

BC risk according to HT regimen

0,0 1,0 2,0 3,0 4,0

0 50 55 60 65 50 55 60 65 50 55 60 65 50 55 60 65 50 55 60 65

Adjusted HR, 95% CI Estrogen Long cyc Cyc com Cont com Tibolone

DaHoRS/07

BC risk according to route

1 2 3

50 55 60 65 50 55 60 65 50 55 60 65 50 55 60 65

Adjusted HR, 95% CI Oral E Oral comb TD Estrogen TD comb.

DaHoRS/07

The impact of progestagen dose

Low = 0.5mg NETA or 2.5mg MPA. High = 1mg NETA or 5mg MPA

0,41 1,04 0,91 1,38 2,28 2,86 1,77 2,99 0,0 0,5 1,0 1,5 2,0 2,5 3,0 3,5

Never Low p High p Low p High p Low p High p Low p High p

DaHoRS/07

Adjusted RR, 95% CI 51-54 55-59 60-64 65-69 All continuous combined regimens

1,0 1,4 2,0 2,0 1,2 1,9 2,5 2,4 1,0 1,2 2,2 1,4

0,5 1,0 1,5 2,0 2,5 3,0 3,5 4,0

51-54 55-59 60-64 65-69 51-54 55-59 60-64 65-69 2mg E2, 1mg NETA 4mg E2, 1mg NETA 1.5mg E2, 10mg MPA

DaHoRS/07

Adjusted HR, 95% CI

BC risk acc to progestagen type and estrogen dose.

Cyclic combined regimen

1,0 1,3 1,2 1,0 1,1 0,9 1,0 1,1 1,0

1,0 1 2 3

Never 95-72 71-60 59-48 47-36 35-24 23-12 11-9 8-6 5-3 2-0 Curr

Months since last use All 51-54 55-59 60-64 65-69

Adjusted RR, 95% CI

Previous systemic use and BC risk

DaHoRS/07

1 0,4 0,3 0,4 0,7 0,5 0,5

1 2

Never Estrogen Long cycle Cycl comb Cont comb Tibolone All

DaHoRS/07

Adjusted RR, 95% CI

Case-fatality rate 5 yrs after diagnosis

Women with BC: 12,831 Dead after diagnosis: 2,347 (18%) Five years follow-up: 1,269

1 0,81

0,5 1,0 1,5

Never Ever HT

DaHoRS/07 Adjusted RR, 95% CI

Risk of lethal BC with hormones within five years after diagnosis

Women with BC: 12,831 Dead after diagnosis: 2,347 (18%) Five years follow-up: 1,269

BC screening, HT and BC

• Cohort study among screening participants
• Enrolment period: 1995-2004
• Questionnaire at enrolment
• Follow-up 2 years (up to next BC screening)
• Included: 296,651 women.
• Detection of screening BC: 1,512
• Detection of interval BC: 814
• Confounders: menarche, education, number
• f births, family history, alcohol, menopause

Hofvind S et al. Int J Cancer 2006; 118: 3112-7.

Hofvind: Results

Screen BC Interval BC Never HT ref ref HT <1 year 1.1 (0.9-1.3) 1.2 (0.9-1.6) HT 1-4 years 1.5 (1.3-1.7) 1.8 (1.5-2.2) HT 5-9 years 1.7 (1.4-2.1) 2.8 (2.2-3.5) HT ≥10 years 1.9 (1.5-2.5) 2.9 ((2.1-4.0) Ever HT 1.5 (1.3-1.6) 1.9 (1.6-2.2) +HT, grade III 14% 27%

• HT, grade III 17%

36%

Hofvind Solveig et al. Int J Cancer 2006; 118: 3112-7.

Hofvind: Comments/questions

• Overall risk ratio of 1.6 with HT as in MWS
• Expected that interval BC are more

aggressive and more advanced than screening cancers (with and without HT)

• BC after HT are less aggressive than BC in

women never on HT (lower grade)

• Survival data missing
• We have to expect fewer BC events from

2003 as compared with 2002.

Hofvind S et al. Int J Cancer 2006; 118: 3112-7.

BC incidence in Norway 1996-2005

2352 2403 2416 2409 2527 2622 2696 2723 2786 2780

2000 2200 2400 2600 2800 3000

1 9 9 6 1 9 9 7 1 9 9 8 1 9 9 9 2 2 1 2 2 2 3 2 4 2 5

Cancer Registry, Norway

Incidence per 100,000

BC incidence rate Norway 2002 and 2005

104 236 307 330 312 1 96 226 270 305 272 3 13 50 164 267 235 202 321 6 21 55 179 323 252 212 332

50 100 150 200 250 300 350 400

< 1 5 1 5

• 1

9 2

• 2

4 2 5

• 2

9 3

• 3

4 3 5

• 3

9 4

• 4

4 4 5

• 4

9 5

• 5

4 5 5

• 5

9 6

• 6

4 6 5

• 6

9 7

• 7

4 7 5

• 7

9 8

• 8

4 8 5 +

Cancer Registry, Norway

Incidence per 100,000

Latest news

Oral contraceptives – HT – breast cancer

• Cohort study
• OC and HT history at baseline in 1996/97/98
• Follow up in cancer registry until end of 2004
• Follow up time: On average 7 years.
• Cohort size: 30,118 women born 1927-57
• Incident BC: 540 during 209,661 person yrs.
• Confounders: Family history, BMI, menarche,

age at first birth, parity.

• Ever OC: 38%. Ever HT: 45%

Lund Eiliv et al. Int J Cancer 2007; Early view.

Lund et al: Results

HT Never OC Ever OC All Never HT ref 1.1 (0.8-1.5)

• Prev. HT

0.9 (0.5-1.4) 0.9 (0.4-1.6) Current HT 1.5 (1.2-2.0) 2.3 (1.8-3.0) 1.95 Current ET 0.9 (0.5-1.6) 2.6 (1.7-4.2) Current EPT 2.0 (1.5-2.6) 2.6 (1.9-3.4) Conclusion: Women previously on OC have a higher risk of BC with HT that women never

• n OC.

Lund E et al. Int J Cancer 2007; Early view.

Lund et al: Comments/questions

• No update on exposure since enrolment
• Same risk for ET and EPT
• Previous OC no HT: No  BC risk
• Previous OC and previous HT: No  BC risk.
• Length of use ?
• Cyclic / continuous combined HT ?
• New studies generally have a high per cent
• f previous OC users.

Lund E et al. Int J Cancer 2007; Early view.

Risk measures

Relative risk:

• Express an instant risk
• No cumulated aspect
• No idea of the absolute risk

Life-time risk

• The best and easiest measure to understand
• Expresses the cumulated risk
• Expresses the absolute risk

Breast cancer: Etiologic fraction of HT

50 100 150 200 250 300 350 400

<15 15- 19 20- 24 25- 29 30- 34 35- 39 40- 44 45- 49 50- 54 55- 59 60- 64 65- 69 70- 74 75- 79 80- 84 85+

Etiological fraction: All: 3% All >50 years: 4% Incidence per 100,000

Health Statistics, National Board of Health, Denmark Li/07

HT and breast cancer: Conclusion

Breast cancer Life-time risk All women 10% No family BC, no HT 8% Mother or sister BC, no HT 16% All women without HT 9.7% ET in five years 9.8% (+0.1) ET in 10 years 10,2% (+0.5) EPT in five years 10.2% (+0,5) EPT in 10 years 10,8% (+1,1) Concl: About 1 more/100 wom 10 yrs on HT

Li/07 DSOG guidelines 2005

Lifetime risk of breast cancer after dif. exposures from 50 years

6 6,5 8 9,7 10 10,2 10,8 11 14 16 4 6 8 10 12 14 16

P h y s . A c t F i r s t b i r t h 2 y A l l n

• n

d i s p A l l w i t h

• u

t H R T A l l w

• m

e n H T 5 y r s H T 1 y r s 2 d r i n k s / d A d i p

• s

i t y F a m . D i s p

Li/07

Hormone therapy; an update

• Hormone use
• HT - breast cancer
• HT - endometrial cancer
• HT - ovarian cancer
• HT - colo-rectal cancer
• HT - heart and circulation
• HT - death
• Conclusion

Endometrial cancer in DK

Incidence: 600/year, deaths: 80 per year

5 10 15 20 25

0-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+

Per cent distribution

20 40 60 80 100

Incidence per 100,000

Lifetime risk: 1,7% 7% / 93%

Danish Cancer Society, Division of Cancer Epidemiology

Endometrial cancer: Risk factors

HT Smoking Nulliparity Endometrial cancer Diabetes Adiposity Hypertension Early menarche Late menopause

Endometrial cancer in DK

Incidence: 600/year, deaths: 100 per year

1,7 2,1 3,3 12,6 1 1,4 1 2,7 3,5 1 3,2 2 0,7 8,4

0,1 1 10 100

N e v e r E s t r

• g

e n

• n

l y < 2 y e a r s 2

• 4

y e a r s 5

• 9

y e a r s 1

• 1

4 y e a r s > 1 4 y e a r s C y c l i c C

• n

t i n u

• u

s < 2 y e a r s 2

• 4

y e a r s 5

• 9

y e a r s 1

• 1

4 y e a r s > 1 4 y e a r s

Relative risk of EC. 95% CI

Swedish case-control study. Controls: 3,368 women. Cases: 709 women 50-74 years with endometrial cancer Weiderpass et al. J Natl Canc Inst 1999; 91: 1131-7

Estrogen only Estrogen-progestagen

HT and endometrial cancer

1,5 1,05 1,8 0,75

0,1 1 10

Never ET EPT cy EPT cont Tibolone Relative risk of EC. 95% CI

Cohort study. 716.738 women followed. Cases: 1,320 with endometrial cancer

• MWS. Lancet 2005: 365: 1543-51

Hormone therapy; an update

• Hormone use
• HT - breast cancer
• HT - endometrial cancer
• HT - ovarian cancer
• HT - colo-rectal cancer
• HT - heart and circulation
• HT - death
• Conclusion

Ovarian cancer: Risk factors

Nulliparity (RR 2) OC (RR 0.7) Ovarian cancer Infertility (RR 1.7) Sterilisation (RR 0.6) Family ov. Cancer (RR 2-4) HT Hysterectomy (RR 0.7)

HT and ovarian cancer

• Case-control study, Sweden 1993-95
• 655 women with epithelial ovarian cancer
• 3,899 population controls 50-74 years old
• Included variables: HT, OC use, age at

menarche, age at menopause, parity, age at first birth, breastfeeding, abortions, BMI, tubal ligation, hysterectomy, family ovarian cancer, family breast cancer, infertility.

Riman et al. Am J Epidemiol 2002; 156: 363-73

HT and ovarian cancer

1,4 1,5 1 0,6 0,8 1 1,2 1,4 1,6 1,8 2

ET EPTcyc EPTcon

Ever use versus never use

Riman et al. J Natl Canc Inst 2002; 94: 497-504

HT and cancer of ovary (CO)

Conclusion

• Epidemiologic findings may be explained by

retrograde transportation of contaminants

• HT implying bleeding may thus extend the

period during which the ovaries are exposed to contaminants.

• A regimen on 1-2 years cyclic HT followed by

continuous HT don’t confer risk of CO.

Riman et al. Am J Epidemiol 2002; 156: 363-73

Hormone therapy; an update

• Hormone use
• HT - breast cancer
• HT - endometrial cancer
• HT - ovarian cancer
• HT - colo-rectal cancer
• HT - heart and circulation
• HT - death
• Conclusion

Colo- rectal cancer in DK

Incidence: 1.500/year, deaths: 900/year (60%)

5 10 15 20 25 30

<20 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80+

Per cent distribution

20 40 60 80 100 120

Incidence per 100,000

Lifetime risk: 2.5% 6% / 94%

Danish Cancer Society, Division of Cancer Epidemiology

Colon cancer and HT

0,8

0,1 1 10

Ever (1) Ever (2) <5 years (3) 5-14 years (3) >14 years (3) Ever (4) Ex-use (5) Ever (5) Current (5) Ever (6) Ex-use (7) Ever (7) Current (7) Ever (8) Ex-use (9) Ever (9) Current (9) Ex-use (10) Ever (10) Current (10) Ever (11) Pragmatic mean

Lifetime risk: 2.5%

Rectum cancer and HT

0,7

0,1 1 10

Ever (1) Ever (2) Ever (3) Ever (4) Ex-use (5) Ever (5) Current (5) Ever (6) Ever (7) Ex-use (8) Ever (8) Current (8) Ever (9) Pragmatic mean

WHI results

EPT ET 50-59

• Coronary heart disease

1.3 0.9 0.6

• Stroke

1.4 1.4 1.1

• Venous thromboembolism

2.1* 1.3 1.2

• Breast cancer

1.3 0.8 0.7

• Endometrial cancer

0.8 hysterect.

• Colorectal cancer

0.6 1.1 0.6

• Hip fracture

0.7 0.6 NA

• Vertebral fracture

0.7 0.6 NA

• All cause mortality

1.0 1.0 0.7

HT og colo-rectal cancer

Conclusion

• ET as well as EPT protects against colon

and rectum cancer.

• The protection fades out five years after

stopping with HT

• The protection is about 30-40%
• No difference in protection between ET

and EPT.

HT and cancer: Conclusion

• Breast: Increased risk after 5 yrs

EPT confers higher risk than ET

• Endometrium: ET increases the risk

EPTcycl a little, EPTcon no increased risk

• Ovary: Slightly increased risk after 5 yrs

use of ET or EPTcycl, EPTcont. no risk

• Colon-rectum: 30-40% protection after

five years of use. Same influence from ET and EPT.

Hormone therapy; an update

• Hormone use
• HT - breast cancer
• HT - endometrial cancer
• HT - ovarian cancer
• HT - colo-rectal cancer
• HT - heart and circulation
• HT - death
• Conclusion

AMI in women and men in DK

400 800 1200 1600 2000 2400 2800 3200

15- 19 20- 24 25- 29 30- 34 35- 39 40- 44 45- 49 50- 54 55- 59 60- 64 65- 69 70- 74 75- 79 80- 84 85- 89 90- 94 95+

Incidence per 100,000 per year Videbæk J, Madsen M. 2004 Hjertestatistik

♂ ♀

AMI in women and men in DK

400 800 1200 1600 2000 2400 2800 3200

15- 19 20- 24 25- 29 30- 34 35- 39 40- 44 45- 49 50- 54 55- 59 60- 64 65- 69 70- 74 75- 79 80- 84 85- 89 90- 94 95+

1 2 3 4 Incidence per 100,000 per year Videbæk J, Madsen M. 2004 Hjertestatistik

♂ ♀

Incidence rate ratio Men/won

AMI in women and men in DK

1 10 100 1000 10000

15- 19 20- 24 25- 29 30- 34 35- 39 40- 44 45- 49 50- 54 55- 59 60- 64 65- 69 70- 74 75- 79 80- 84 85- 89 90- 94 95+

Incidence per 100,000 per year Videbæk J, Madsen M. 2004 Hjertestatistik

♂ ♀

HT and myocardial infarction

0,7

0,1 1 10

Wilson 85, ever Avila 90, current Stampfer 91, current Henderson 91, current Henderson 91, ever Grodstein 96 O, curr Grodstein 96 O+P, cur Ross 81 ever Adam 84 current Adam 84 ex-use LaVecchia 87 current LaVecchia 87 ex-use Beard 89 ever Croft 89 ever Thomsen 89 ever Avila 90 current Avila 90 ex-use Rosenberg 93 O+P, ever Rosenberg 93 O, ever Falkeborn 95 ever Pragmatic mean

Heart and oestrogen/progestin replacement study (HERS)

Design: Randomised blinded placebo- controlled secondary prevention trial Material: 2,763 women with coronary heart disease, younger than 80 years. Mean: 67y Method: Randomisation between placebo and 0.625mg estrogen + 2.5mg MPA. HERS I: Follow up 4.1 years (randomised) HERS II: Follow up 6.8 years (not randomised) Outcome: Fatal and non-fatal new AMI.

Hulley et al. JAMA 1998; 280: 605-13 Grady et al. JAMA 2002; 288: 49-57

HERS: results

Estr-prog1 Placebo RR 95% CI n 1380 1383 CHD2 I 179 182 1.0 0.8-1.2 CHD I+II 290 293 1.0 0.8-1.2 Fatal I+II 132 122 1.1 0.9-1.4 Nonfatal AMI 183 196 0.9 0.8-1.2 Conclusion: Comb. HT has no influence on the risk of a new AMI after the first AMI.

1) Oestr-prog = conjugated estrogen 0.625mg + medroxyprogesterone acetate 2.5mg 2) CHD: coronary heart disease (=AMI)

HERS: discussion

• All the women had atherosclerotic vessel

walls on which the beneficial influence of

• estrogen in preventing these plaque

formation may not appear.

• MPA may have counterbalanced a positive

influence from oestrogen.

• Concl: CHD is not an indication for HT.

WHI results

EPT ET 50-59

• Coronary heart disease

1.3 0.9 0.6

• Stroke

1.4 1.4 1.1

• Venous thromboembolism2.1* 1.3

1.2

• Breast cancer

1.3 0.8 0.7

• Endometrial cancer

0.8 hysterect.

• Colorectal cancer

0.6 1.1 0.6

• Hip fracture

0.7 0.6 NA

• Vertebral fracture

0.7 0.6 NA

• All cause mortality

1.0 1.0 0.7

Rossouw et al. JAMA 2002; 288: 321-33 & 2004: 291: 1701

Womens health initiative (WHI)

EPT vs placebo ET vs placebo Age: 50-79 50-79, -uterus Number: 16,608 10,739 Regimen: 0.6mg CEE/MPA 0.6mg CEE Follow up: 5.2 yrs, 6.8 yrs Averag age: 63 years 64 years >60 years 2/3 70% Hypertension 36% 48% BMI ≥25: 70%, 80% BMI ≥30: 34% 45%

Rossouw et al. JAMA 2002; 288: 321-33 & 2004: 291: 1701

AMI & HT: Sub group analysis

• WHI. Oestrogen + progestin

0,95 2 1,45 1,2 1,3 1,1 1,1 1,3

0,5 1 1,5 2 2,5 3 3,5 4 4,5 5

+Flash

• Flash

+ DM

• DM

+ Hyp

• Hyp

+ Smo

• Smo

Manson et al. N Engl J Med 2003; 349: 523-34

Hazard ratio, 95% CI

HT & AMI: Danish nurse cohort

Design:

• 23,178 Danish nurses >45 years were

invited to a follow-up study in 1993

• 19,898 (86%) accepted the invitation
• 13,084 (56%) were included in the analysis

after exclusion of pre-menopausal women and women with previous thrombosis

• Exposures assessed at inclusion through

questionnaires

Løkkegaard E et al. BMJ 2003; 326: 426-30

Ellen Løkkegaard: HT & AMI

AMI: n=108 RR 95% CI

• Never HT

1.0

reference

• Current HT

1.0

0.6-1.7

• Current oestrogen

1.0

0.5-1.9

• Current oestrog-progest.

1.1

0.5-2.2

Stratified according to DM AMI: -DM, current vs never 0.8

0.4-1.4

AMI:+DM, current vs never 9.1

2.0-41

IHD: -DM, current vs never 1.2

0.9-1.6

IHD:+DM, current vs never 4.2

1.4-12

HT and AMI: Conclusion

• Observational studies: RR: 0.7-1

Randomised studies: RR: 0.6-1.3

• Previous AMI is not an indication for HT
• ET may reduce the risk more than EPT.
• It is a long term effect, measurable only

after five years. Most likely mechanism:

• Delayed arteriosclerosis in healthy
• Accelerated thrombosis in atherosclerotic

Hormone therapy; an update

• Hormone use
• HT - breast cancer
• HT - endometrial cancer
• HT - ovarian cancer
• HT - colo-rectal cancer
• HT - heart and circulation
• HT - death
• Conclusion

Metaanalysis on HT and death

0,68 1,11 0,69 1,07 0,44 0,68 0,61 1,03

0,2 0,4 0,6 0,8 1 1,2 1,4

CVD Cancer Other Total CVD Cancer Other Total

<60 >60

OR, 95% CI

Aim: HT, deaths, age Meta-analysis on 30 RCT 26,708 participants Salpeter et al. J Gen Intern Med 2004; 19: 791-804

Clinical recommendations

• HT demands an indication
• Best documented epidemiological benefit is
• steoporosis and colon cancer prevention
• Start on a low dose cyclic comb. therapy
• Shift after 2 yrs to cont. comb. therapy
• Lowest available progestagen dose
• Estrogen dose of less significance
• But low dose of estrogen provides feasibility

for a low progestagen dose.

Clinical recommendations

• Best documented risk: BC (incidence)
• Re-evaluation of treatment with few years

interval.

• Women on high-dose preparations should

be shifted to low-dose preparations.

• A good indication if treatment >5 years

Li/03