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La terapia ormonale sostitutiva: sostituire che cosa? Catania, 26 ottobre 2006. Terapia ormonale sostitutiva e rischio oncologico. Prof. A.Gadducci Dipartimento di Medicina della Riproduzione, Divisione di Ginecologia e Ostetricia, Sezione Interna di Ginecologia Oncologica, Università di Pisa.

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La terapia ormonale sostitutiva: sostituire che cosa? Catania, 26 ottobre 2006

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La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

La terapia ormonale sostitutiva: sostituire che cosa?

Catania, 26 ottobre 2006

Terapia ormonale sostitutiva e rischio oncologico

Prof. A.Gadducci

Dipartimento di Medicina della Riproduzione, Divisione di Ginecologia e Ostetricia, Sezione Interna di Ginecologia Oncologica, Università di Pisa


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

La terapia ormonale sostitutiva: sostituire che cosa?

Terapia ormonale sostitutiva e rischio oncologico

  • Breast cancer

  • Endometrial cancer

  • Ovarian cancer


Estrogens and breast cancer

Estrogens and breast cancer

Estrogens may:

  • stimulate cell proliferation and increase the numbers of errors occuring during DNA replication

  • cause DNA damage via their genotoxic metabolites produced during oxidation reactions

  • induce expression/activation of h-TERT, growth factors, matrix metalloproteinases and VEGF


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

IGF-I and breast cancer

Estrogens

Insulin

TGF-

EGF

Antiestrogens

Glucocorticoids

TGF-ß

StimulateInhibit

IGF-secretion


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

IGF-I and breast cancer

  • Breast cancer patients show elevated plasma IGF-I

  • IGF-I serum levels increases with tumor size

  • IGF-I levels higher in women with cancer recurrence

  • Survival probability greater in patients with plasma

  • IGF-I levels < 120 ng/ml

Vadgama et al, (Oncology 1999)


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Thymidine labeling index in normal breast epithelium during different phases of the menstrual cycle

authors weeks of menstrual cycle

1 2 3 4

Meyer(1977) 0.17% 0.17% 0.79% 0.79%

Anderson (1989) 0.51% 0.37% 0.78% 1.25%

Williams (1991) 1.8% 1.5% 3.4% 3.6%


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Progestins and breast cancer cell mitosis

T- 47D and MCF-7 breast cancer cell lines

Progestins induced an initial increase in the number of S-phase cells, but 12h later a reduction occurred so that after 24h the percentage of cells in S-phase was lower than baseline and was maintained at 96h

Clarke and Sutherland, 1996; Musgrove et al, 1991


A re analysis collaborative group on hormonal factors in breast cancer lancet 1997

A re-analysis:Collaborative Group on Hormonal Factors in Breast Cancer (Lancet 1997)

  • Collaborative combined re-analysis

  • More rigorous than a standard meta-analysis

  • 51 studies world-wide

  • 51.000 cases / 108000 controls

  • no statistical evidence of variation in the results across the studies

  • 80% of users had taken oestrogens alone, and there was no evidence of variation according to type of HRT preparation


A re analysis collaborative group on hormonal factors in breast cancer lancet 19971

The risk increased with increasing duration of use (+ 2.3%/year)

roughly equivalent to the increase associated with delaying menopause by a year

The effects of HRT on breast cancer disappeared 5 years after ceasing use

A re-analysis:Collaborative Group on Hormonal Factors in Breast Cancer (Lancet 1997)


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Breast cancer cases in 1000 women aged 50 over the next 20 years

non HRT users45

HRT 5 yrs47

HRT 10 yrs 51

HRT 15 yrs57

Collaborative group on Hormonal Factors in Breast cancer, Lancet, 1997


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Obesity and breast cancer risk

in postmenopausal women

Conversion androgens estrogens

SHBG levels

  • Breast cancer risk increases from the basal individual risk by 2.3% for each use of ERT, but this increase seems to be almost entirely limited to lean women

  • Overweight postmenopausal women alredy have achieved the maximun hormone-related risk to their endogenous production of estrogens


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Cythocrome P450 gene polymorfism, HRT and BC risk

  • In a case-control study (1521 BC cases and 1498 controls), CYP1B1 gene polymorfism did not influence overall BC risk.

  • However, women who had taken HRT for > 4 yrs and carried a particular CYP1B1 genotype (CYP1B1*3/*3) had a RR of BC of 2.0 (95% CI 1.1-3.5) compared with long-term HRT users without this genotype

From Rylander-Rudqvist, 2003


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

(1.0-1.5)

(1.0-1.6)

(1.0-1.5)

(1.0-1.3)

(0.5-1.6)

RR of breastcancer

716/196666

805/179401

162/29564

11/3048

130/24757

101/17428

No use

E-P(?)

E

P

E-P

E and E-P

Menopausal Estrogen and Estrogen-Progestin Replacement Therapy and Breast Cancer Risk (all data)

Modified from Schairer et al, JAMA 2000; 283: 485-491


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

(CI 1.07-1.45)

(CI 1.02-1.18)

(CI 0.97-1.15)

(CI 1.13-1.68)

(CI 0.88-1.35)

Effects of Hormonal Replacement Therapy on Breast Cancer Risk: Estrogen Versus Estrogen Plus Progestin over 5 yrs

Hormone Replacement Therapy: HRT

Estrogen replacement therapy: ERT

Estrogen progestin replacement therapy: EPRT

Continuous combined replacement therapy: CCRT

Sequential estrogen + progestin therapy: SEPRT

From Ross RK et al, 2000


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Risks and benefits of estrogen plus progestin in healthy postmenopausal women (Women’s Health Initiative [WHI] randomized controlled trial)

16.608 postmenopausal women aged 50-79 with an intact uterus were randomized by 40 US centers in 1993-1998

Randomization

Placebo

CE 0.625 mg/die+MPA 2.5 mg/die

2002


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Risks and benefits of estrogen plus progestin in healthy postmenopausal women (WHI)

After a median 5.2 follow-up

HR ( 95% CI)

Coronary heart disease 1.29 (1.02-1.63)

Stroke 1.41 (1.07-1.85)

Pulmonary embolism 2.13 (1.39-3.25)

Breast cancer 1.26 (1.00-1.59)

Colorectal cancer 0.63 (0.43-0.92)

Endometrial cancer 0.83 (0.47-1.47)

Hip fracture 0.66 (0.45-0.98)

Death due other causes0.92 (0.74-1.14)


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Risks and benefits of estrogen plus progestin in healthy postmenopausal women (WHI)

Absolute excess risks per 10.000 person-years attributable to E+P

  • 7 more coronary heart disease events

  • 8 more strokes

  • 8 more pulmonary embolisms

  • 8 more invasive breast cacers

  • 6 fewer colorectal cancers

  • 5 fewer hip fractures

2002


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

WHI trial: Critical questions

  • 26% of women were current or past hormone users and 1/3 of them for > 5 years.

  • The risk for breast cancer was increased only in those women previously treated with hormones.

  • In never users before entering the study, the HR for breast cancer was 1.06 after 5.2 years of HRT.

  • MPA is a very potent down regulator of the estrogen receptor.

  • HRT is a collective name, but not all types of HRT are the same.


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Effects of CE in postmenopausal women with hysterectomy: WHI randomised controlled trial

10.739 postmenopausal women aged 50-79 with prior hysterectomy randomized by 40 US centers

Randomization

Placebo

CE 0.625 mg/die

2004


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Risks and benefits of CE in postmenopausal women with hysterectomy (WHI trial)

After a median 6.8 follow-up

HR ( 95% CI)

Coronary heart disease 0.91 (0.75-1.12)

Stroke 1.39 (1.10-1.77)

Pulmonary embolism 1.34 (0.87-2.06)

Breast cancer 0.77 (0.59-1.01)

Colorectal cancer 1.08 (0.75-1.55)

Hip fracture 0.61 (0.41-0.91)

2004


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Million Women Study

1.084.110 UK women aged 50-64 years with an intact uterus were recruited

breast cancer RR (95% CI)

Current HRT use1.66 (1.58-1.75)

Estrogen alone1.30 (1.22-1.38)

Estrogen/progestin2.00 (1.91-2.09)

Tibolone1.45 (1.25-1.67)

Beral 2003


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Million Women Study

breast cancer RR (95% CI)

Never users of HRT1.00(0.96-1.04)

Past users of HRT

< 1 year0.94 (0.84-1.05)

1-4 years1.01 (0.92-1.12)

5-9 years1.14(1.00-1.30)

>10 years1.05 (0.84-1.30)

Beral 2003


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Million Women Study

breast cancer RR (95% CI)

Current use of estrogen-progestin combinations

< 1 year1.45 (1.19-1.78)

1-4 years1.74 (1.60-1.89)

5-9 years2.17 (2.03-2.33)

>10 years2.31 (2.08-2.56)

Beral 2003


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Million Women Study

Duration use < 5 yearsDuration use > 5 yearsRR (95% CI) RR (95% CI)

Sequential 1.77 (1.59-1.97)2.12 (1.95-2.30)

Continous 1.57 (1.37-1.79)2.40 (2.15-2.67)

Beral 2003


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Million Women Study

breast cancer RR (95% CI)

Current use estrogen alone

< 1 year0.81 (0.55-1.20)

1-4 years1.25 (1.10-1.41)

5-9 years1.32 (1.20-1.46)

>10 years1.37 (1.22-1.54)

Beral 2003


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Breast cancerrisk and HRT with progestins other MPA

Cohort study including 3175 women (mean follow-up= 8.9 years)

83%of them received TTS estradiol + progestin other than MPA

RR (95% CI) 0.98 0.65-1.5

Cohort study including 54548 women (mean follow-up= 5.8 years)

RR95% CI

estrogen alone 1.1 0.8-1.6

estrogen + synthetic progestin 1.4 1.2-1.7

estrogen + micronized progesterone0.9 0.7-1.2

De Lignieres 2002

Fournier 2004


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

La terapia ormonale sostitutiva: sostituire che cosa?

Terapia ormonale sostitutiva e rischio oncologico

  • Breast cancer

  • Endometrial cancer

  • Ovarian cancer


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Endometrial carcinoma

Type-1 Type-2

HistologyEndometrioidNon endometrioid

OriginAtypical hyperplasia Intraepithelial carcinoma

EndocrineEstrogen-dependentEstrogen-statusindependent

P53-statusWild-typeMutated

PrognosisGoodPoor


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

5-year survival in EC by histotype

pts (n) 5-year survival HR (95%CI)

Endometrioid623181.2% reference

Adenosquamous31776.1% 1.1 (0.9-1.4)

Mucinous7476.2%0.9 (0.6-1.5)

Serous33548.4%1.7 (1.4-2.0)

Clear cell18559.7%1.6 (1.2-2.0)

25th Volume Annual Report, 2003


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Postmenopausal endogenous estrogens and risk of EC

VariablescasescontrolsRR (95% CI)p value

E1 (pg/ml)

<2010831.0

20-2819792.1(0.9-4.8)

>2827563.9(1.8-8.7)< 0.001

SHBG (nMol/L)

<44.326671.0

44.3-64.418740.6(0. 3-1.2)

>64.413800.39(0.18-0.84) 0.01

From Zeleniuch-Jacquotte, 2001


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Postmenopausal endogenous estrogens and risk of EC

VariablescasescontrolsRR (95% CI)p value

E2 (pg/ml)

<614771.0

6-816801.1(0.52-2.4)

>827612.4(1.1-4.9)0.02

Free E2 (%)

<1.1013781.0

1.10-1.2813841.1(0. 44-2.4)

>1.2831603.5(1.6-7.5)< 0.001

From Zeleniuch-Jacquotte, 2001


Insuline like growth factor igf in endometrium

Insuline like growth factor (IGF) in endometrium

  • IGF are predominantly synthetized by the stromal cells

  • IGF expression is up- regulated by estrogens

  • IGF- receptors are up- regulated by progesterone


Insuline like growth factor binding protein igf bp mrna in the endometrium

Insuline-like growth factor binding protein (IGF-BP) mRNA in the endometrium

IGF-BP 1 high expression in late secretory phase

IGF- BP 2 no cyclic change

IGF- BP 4 no cyclic change

IGF- BP 5 no cyclic change

IGF- BP 6 high expression in late secretory and

early proliferative phase

From Rutanen et al, 1994


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

IGFBP-1 expression and endometrial cancer

Hyperinsulinemia

Progesterone absence

  • Obesity

  • Hypertension

  • Early stages of non-

  • Insulin dependent diabetes

  • Anovulatory cycle

  • Postmenopause

IGFBP-1 expression

unopposed stimulation of endometrial cells by IGF

uncontrolled cell proliferation


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

HRT and EC risk: A meta-analysis

Study selection: 30 studies with adequate controls and risk estimates

RR95% CI

Unopposed estrogen users2.32.1-2.5

Duration of use

< 1 years1.41.0-0.8

1-5 years2.82.3-3.5

5-10 years5.94.7-7.5

10 years9.57.4-12.3

Regimen

Intermittent and cyclic3.02.4-3.8

Continuous2.92.2-3.8

From Grady et al. 1995


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

HRT and EC risk: A meta-analysis

RR95% CI

Type of estrogen

Conjugated2.52.1-2.9

Synthetic1.31.1-1.6

Dose of conjugated estrogen (mg)

0.33.91.6-9.5

0.6253.42.0-5.6

>1.255.84.5-7.5

Time since last use (years)

<14.12.9-5.7

1.43.72.5-5.5

>52.31.8-3.1

From Grady et al. 1995


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Incidence of hyperplasia in HRT users:

Relationship with the length of progestin use

Length of progestin use Incidence of hyperplasia

7 days4 %

10 days 2 %

12 days 0 %

Whitehead and Fraser, 1987


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Postmenopausal Estrogen/ Progestin Interventions

(PEPI ) trial

From Writing Group for the PEPI trial , 1996

Hyperplasia

ptssimple complex atypical

% % %

Placebo1190.8 0.8 0.8

CE 0.625 mg/day119 27.7 22.7 11.8

CE +MPA 10 mg

for 12 days 118 3.4 1.7 0

CE +MPA

2.5 mg /day 1200.8 0 0

CE +MP 200 mg

for 12 days 120 4.2 00.8


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Antiestrogenic activity of progestins

  • Down-regulation of ER

  • Enhanced conversion of estradiol to estrone

  • Down-regulation of bcl-2 expression

  • Suppression of estrogen-induced expression of VEGF

  • Stimulation of IGF-BG

  • Inhibition of the estrogen-induced activation of hTERT expression


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Postmenopausal estrogen plus progestin use and risk of EC

RR95% CI

Gambrell 1980 cohort 0.20.1-0.6

Persson 1989 cohort 0.20.1-0.6

Voigt 1991 case-control 1.60.6-3.9

Jick 1993 case-control 1.90.9-3.8

Brinton 1993 case-control 1.80.6-4.9

Grady 1995 meta-analysis cohort 0.40.2-0.6

Grady 1995 meta-analysis case-control 1.81.1-3.1

WHI2002 randomized trial 0.830.47-1.47

MWS2005 cohort0.710.56-0.9 Strom2006 case-control0.80.6-1-1


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Risks and benefits of estrogen plus progestin in healthy postmenopausal women (WHI)

After a median 5.2 follow-up

HR ( 95% CI)

Coronary heart disease 1.29 (1.02-1.63)

Stroke 1.41 (1.07-1.85)

Pulmonary embolism 2.13 (1.39-3.25)

Breast cancer 1.26 (1.00-1.59)

Colorectal cancer 0.63 (0.43-0.92)

Endometrial cancer 0.83 (0.47-1.47)

Hip fracture 0.66 (0.45-0.98)

Death due other causes0.92 (0.74-1.14)


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Risk of endometrial cancer by days/ month progestin used

CasesControls

N NOR (95% CI)

Never used2705931.0

Progestin added 25263.1 (1.7-5.7)

< 10 days/mo.

Progestin added 25641.3 (0.8-2.2)

10-21 days/mo.

Beresford et al. Lancet 1997


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Case-control study of HRT and EC

US population-based case-control study: 511 EC cases aged 50-79 yrs 1412 random-digit-dialing controls

OR (95% CI)

ERT > 3 yrs3.4(1.4-8.3)

HRT any duration0.8(0.6-1.1)

HRT > 3 yrs vs ERT > 3 yrs 0.2(0.1-0.6)

Strom, 2006


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

ccHRT and EC: RR (95% CI)

ERTscHRT ccHRT

Pike, 19972.2 (1.9-2.5)1.9 (1.3-2.7) 1.1 (0.8-1.4)

1.1 (0.8-1.4)

Weiderpass, 19996.2 (3.1-12.6) 2.9 (1.8-4.6) 0.2 (0.1-0.8)

Hill, 2000 0.6 (0.3-1.3)


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

La terapia ormonale sostitutiva: sostituire che cosa?

Terapia ormonale sostitutiva e rischio oncologico

  • Breast cancer

  • Endometrial cancer

  • Ovarian cancer


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

HRT and risk of EOC

INCREASED INCIDENCE

NO YES

La Vecchia 1982 Cramer 1983

Smith 1984 Booth 1989

Wu 1988 Kaufman 1989

Hartge1988Whittemore 1993

Purdie1999Rodriquez 1995

Hempling1997Negri 1999

Coughlin2000 Riman 2002

Sit2002Lacey2002


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

HRT and EOC : Re-analysis of 4 European Studies

2 studies conducted in Greece

1 in Italya total of 1470 EOC and

1 in UK3271 hospital records

RR of EOC among HRT users: 1.71 (95% CI 1.30-2.25)

Negri et al. 1999


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Cancer incidence and mortality in women receiving HRT

Population study: cohort of 22.597 Swedish Women.

2230 incident cancer and 848 cancer deaths after 13 years of follow-up

SiteIncidence

OE RR 95% CI

Breast 634 643 1.0 0.9-1.1

Endometrium261 147 1.8 1.6-2.0

Ovary 131 1410.9 0.8-1.1

Colon 153 175 0.9 0.7-1.0

Liver and biliary tract43 73 0.6 0.4-0.8

Melanoma 60 68 0.9 0.7-1.1

Other skin 43 46 0.9 0.7-1.3


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

HRT and risk of EOC

491 pts with EOC , 741 women as controls

RR among HRT users: O.85 (95% CI= 0.6-1.2)

duration EOC controls Odds ratio

(y) 470 70595%CI

None 391 (83.2%) 581 (82.4%) 1.0

<5 54 (11.5%) 74 (10.5%) 0.8 (0.5-1.2)

5-9 16 ( 3.4%) 28 ( 4.0%) 0.6 (0.3-1.1)

>10 9 ( 1.9%) 22 ( 3.1%) 0.6 (0.3-1.4)

Hempling 1997


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Risks and benefits of estrogen plus progestin in healthy postmenopausal women (WHI)

After a median 5.2 follow-up

HR ( 95% CI)

Coronary heart disease 1.29 (1.02-1.63)

Stroke 1.41 (1.07-1.85)

Pulmonary embolism 2.13 (1.39-3.25)

Breast cancer 1.26 (1.00-1.59)

Colorectal cancer 0.63 (0.43-0.92)

Endometrial cancer 0.83 (0.47-1.47)

Hip fracture 0.66 (0.45-0.98)

Ovarian cancer1.58(0.77-3.24)


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

HRT and risk of endometrioid EOC

Increased risk

YES NO

Weiss 1982Booth 1989

La Vecchia 1982Whittemore1992

Hunt 1987Hempling 1997

Purdie 1999


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

HRT and risk of EOC

Australian population-based case-control study

793 cases of EOC between 1990 and 1993

855 female controls

NO clear association between HRT use and HRT risk

Unopposed ERT had a RR =2.56 (95% CI, 1.32-4.94) of

endometrioid or clear cell EOC

Purdie et al. 1999


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

HRT and risk of EOC

Relationship with histologic type

Histologic type Pts Odds Ratio (95% CI)

Serous 61 (61%) 1.2 (0.8-1.7)

Clear cell 5 (5%) 1.1 (0.4-3.4)

Endometrioid 5 (5%) 0.4 (0.2-1.2)

Undifferentiated 29 (29%) 0.8 (0.5-1.2)

Hempling 1997


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

ERT and ovarian cancermortality

Prospective study of 211.581 postmenopausal women

Death rates from ovarian cancer

ERT usersRR (95% CI)

baseline users1.51 (1.16-1.96)

former users1.16 (0.99-1.37)

baseline users >10 years of use2.20 (1.53-3.17)

former users> 10 years1.59 (1.13-2.25)

Rodriquez 2001


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Cancer incidence and mortality in women receiving HRT

Population study cohort of 22.597 Swedish Women.

2230 incident cancer and 848 cancer deaths after 13 years of follow-up

Site Mortality

O E RR 95%CI

Breast 102 196 0.5 0.4-0.6

Endometrium25 30 0.8 0.5-1.2

Ovary 83 99 0.8 0.7-1.0

Colon 62 89 0.7 0.5-0.9

Liver and biliary tract-- - -

Melanoma 8 15 0.5 0.2-1.0

Other skin -- - -


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

ERT/HRT and ovarian cancermortality

Lasey 2002

Cohort-study of partecipants in the Breast Cancer Detection Demonstration Project

44241 postmenopausal women; 321 women developed ovarian cancer

Ovarian cancer RR (95% CI)

Ever ERT use1.6 (1.2-2.0)

ERT for 10 to 19 years1.8 (1.1-3.0)

ERT >20 years3.2 (1.7-5.7)

HRT after prior ERT1.5 (0.91-2.4)

HRT only use1.1 (0.64-1.7)

HRT only use for <2 years1.6 (0.78-3.3)

HRT only use for >2 years0.8 (0.35-1.8)


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

ERT/HRT and ovarian cancermortality

Case-control study:655 ovarian cancer patients

3899 controls (all 50-74 years)

Ovarian cancer OR (95% CI)

Ever ERT use1.43 (1.02-2.00)

Ever sequential HRT1.54 (1.15-2.05)

Ever continous HRT 1.02 (0.73-1.43)

Riman 2000


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Growth response to key reproductives hormones in normal and malignant epithelial ovarian cell

Syed 2001

normal immortalizedcancer

LH, FSH

E2, E1

5-dihydrotestosterone

Testosterone

Progesterone low-dose

Progesterone high-dose


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Estrogen and progesterone as modulators of apoptosis in ovarian epithelial cells

Estrogen Progesterone

Fas/FasL pathway activation

Up-regulation of Bcl-2TGF-β1

TGF- β2/3 caspase-3 activation

+

+

-

caspase-8 activation

+

+

APOPTOSIS


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Conclusion: Breast cancer

  • HRT use for a few years did not change BC risk, that increases progressively only after 5 years of treatment.

  • Different dosages, different routes of administration and different preparations (estrogen alone or estrogen + progestin) may have a significant impact on BC risk.

  • All recent studies seem to show a negative effect of estrogen + progestin on BC risk compared with estrogen alone.


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Conclusion: Endometrial cancer

  • Whereas unopposed ERT significantly increases EC risk, an appropriate combination of estrogen and progestin does not appear to increase and may decrease EC risk, especially for women who receive a continous combined treatment.


La terapia ormonale sostitutiva sostituire che cosa catania 26 ottobre 2006

Conclusion: Ovarian cancer

  • Data from literature concerning the relationship between HRT and OC, are controversial, but appear to exclude an association.

  • Some recent observations appear to suggest a different EOC risk in women receiving ERT and in those receiving HRT.

  • In particular, women treated with continuous combined estrogen/progestin therapy appear to have the lowest risk.


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