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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

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?

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


IGF-I and breast cancer

Estrogens

Insulin

TGF-

EGF

Antiestrogens

Glucocorticoids

TGF-ß

StimulateInhibit

IGF-secretion


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)


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%


Progestins and breast cancer cell mitosis different phases of the menstrual cycle

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: different phases of the menstrual cycleCollaborative 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)


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

non HRT users 45

HRT 5 yrs 47

HRT 10 yrs 51

HRT 15 yrs 57

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


Obesity and breast cancer risk years

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


Cythocrome P450 gene polymorfism, HRT and BC risk years

  • 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


(1.0-1.5) years

(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


( yearsCI 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


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


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 causes 0.92 (0.74-1.14)


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


WHI trial: Critical questions postmenopausal women (WHI)

  • 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.


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


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


Million Women Study hysterectomy (WHI trial)

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

breast cancer RR (95% CI)

Current HRT use 1.66 (1.58-1.75)

Estrogen alone 1.30 (1.22-1.38)

Estrogen/progestin 2.00 (1.91-2.09)

Tibolone 1.45 (1.25-1.67)

Beral 2003


Million Women Study hysterectomy (WHI trial)

breast cancer RR (95% CI)

Never users of HRT 1.00 (0.96-1.04)

Past users of HRT

< 1 year 0.94 (0.84-1.05)

1-4 years 1.01 (0.92-1.12)

5-9 years 1.14 (1.00-1.30)

>10 years 1.05 (0.84-1.30)

Beral 2003


Million Women Study hysterectomy (WHI trial)

breast cancer RR (95% CI)

Current use of estrogen-progestin combinations

< 1 year 1.45 (1.19-1.78)

1-4 years 1.74 (1.60-1.89)

5-9 years 2.17 (2.03-2.33)

>10 years 2.31 (2.08-2.56)

Beral 2003


Million Women Study hysterectomy (WHI trial)

Duration use < 5 years Duration 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


Million Women Study hysterectomy (WHI trial)

breast cancer RR (95% CI)

Current use estrogen alone

< 1 year 0.81 (0.55-1.20)

1-4 years 1.25 (1.10-1.41)

5-9 years 1.32 (1.20-1.46)

>10 years 1.37 (1.22-1.54)

Beral 2003


Breast cancer hysterectomy (WHI trial)risk 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)

RR 95% CI

estrogen alone 1.1 0.8-1.6

estrogen + synthetic progestin 1.4 1.2-1.7

estrogen + micronized progesterone 0.9 0.7-1.2

De Lignieres 2002

Fournier 2004


La terapia ormonale sostitutiva: sostituire che cosa? hysterectomy (WHI trial)

Terapia ormonale sostitutiva e rischio oncologico

  • Breast cancer

  • Endometrial cancer

  • Ovarian cancer


Endometrial carcinoma hysterectomy (WHI trial)

Type-1 Type-2

Histology Endometrioid Non endometrioid

OriginAtypical hyperplasia Intraepithelial carcinoma

Endocrine Estrogen-dependent Estrogen- statusindependent

P53-status Wild-type Mutated

Prognosis Good Poor


5-year survival in EC by histotype hysterectomy (WHI trial)

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

Endometrioid 6231 81.2% reference

Adenosquamous 317 76.1% 1.1 (0.9-1.4)

Mucinous 74 76.2% 0.9 (0.6-1.5)

Serous 335 48.4% 1.7 (1.4-2.0)

Clear cell 185 59.7% 1.6 (1.2-2.0)

25th Volume Annual Report, 2003


Postmenopausal endogenous estrogens and risk of EC hysterectomy (WHI trial)

Variables cases controls RR (95% CI) p value

E1 (pg/ml)

<20 10 83 1.0

20-28 19 79 2.1 (0.9-4.8)

>28 27 56 3.9 (1.8-8.7) < 0.001

SHBG (nMol/L)

<44.3 26 67 1.0

44.3-64.418 74 0.6 (0. 3-1.2)

>64.4 13 80 0.39 (0.18-0.84) 0.01

From Zeleniuch-Jacquotte, 2001


Postmenopausal endogenous estrogens and risk of EC hysterectomy (WHI trial)

Variables cases controls RR (95% CI) p value

E2 (pg/ml)

<6 14 77 1.0

6-8 16 80 1.1 (0.52-2.4)

>8 27 61 2.4 (1.1-4.9) 0.02

Free E2 (%)

<1.10 13 78 1.0

1.10-1.2813 84 1.1 (0. 44-2.4)

>1.28 31 60 3.5 (1.6-7.5) < 0.001

From Zeleniuch-Jacquotte, 2001


Insuline like growth factor igf in endometrium
Insuline like growth factor (IGF) in endometrium hysterectomy (WHI trial)

  • 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


IGFBP-1 expression and endometrial cancer the endometrium

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


HRT and EC risk: A meta-analysis the endometrium

Study selection: 30 studies with adequate controls and risk estimates

RR 95% CI

Unopposed estrogen users 2.3 2.1-2.5

Duration of use

< 1 years 1.4 1.0-0.8

1-5 years 2.8 2.3-3.5

5-10 years 5.9 4.7-7.5

10 years 9.5 7.4-12.3

Regimen

Intermittent and cyclic 3.0 2.4-3.8

Continuous 2.9 2.2-3.8

From Grady et al. 1995


HRT and EC risk: A meta-analysis the endometrium

RR 95% CI

Type of estrogen

Conjugated 2.5 2.1-2.9

Synthetic 1.3 1.1-1.6

Dose of conjugated estrogen (mg)

0.3 3.9 1.6-9.5

0.625 3.4 2.0-5.6

>1.25 5.8 4.5-7.5

Time since last use (years)

<1 4.1 2.9-5.7

1.4 3.7 2.5-5.5

>5 2.3 1.8-3.1

From Grady et al. 1995


Incidence of hyperplasia in HRT users: the endometrium

Relationship with the length of progestin use

Length of progestin use Incidence of hyperplasia

7 days 4 %

10 days 2 %

12 days 0 %

Whitehead and Fraser, 1987


Postmenopausal Estrogen/ Progestin Interventions the endometrium

(PEPI ) trial

From Writing Group for the PEPI trial , 1996

Hyperplasia

pts simple complex atypical

% % %

Placebo 119 0.8 0.8 0.8

CE 0.625 mg/day 119 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 120 0.8 0 0

CE +MP 200 mg

for 12 days 120 4.2 0 0.8


Antiestrogenic activity of progestins the endometrium

  • 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


Postmenopausal estrogen plus progestin use and risk of EC the endometrium

RR 95% CI

Gambrell 1980 cohort 0.2 0.1-0.6

Persson 1989 cohort 0.2 0.1-0.6

Voigt 1991 case-control 1.6 0.6-3.9

Jick 1993 case-control 1.9 0.9-3.8

Brinton 1993 case-control 1.8 0.6-4.9

Grady 1995 meta-analysis cohort 0.4 0.2-0.6

Grady 1995 meta-analysis case-control 1.8 1.1-3.1

WHI 2002 randomized trial 0.83 0.47-1.47

MWS 2005 cohort 0.71 0.56-0.9 Strom 2006 case-control 0.8 0.6-1-1


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 causes 0.92 (0.74-1.14)


Risk of endometrial cancer by days/ month progestin used postmenopausal women (WHI)

Cases Controls

N N OR (95% CI)

Never used 270 593 1.0

Progestin added 25 26 3.1 (1.7-5.7)

< 10 days/mo.

Progestin added 25 64 1.3 (0.8-2.2)

10-21 days/mo.

Beresford et al. Lancet 1997


Case-control study of HRT and EC postmenopausal women (WHI)

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

OR (95% CI)

ERT > 3 yrs 3.4 (1.4-8.3)

HRT any duration 0.8 (0.6-1.1)

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

Strom, 2006


ccHRT and EC: RR (95% CI) postmenopausal women (WHI)

ERT scHRT ccHRT

Pike, 1997 2.2 (1.9-2.5) 1.9 (1.3-2.7) 1.1 (0.8-1.4)

1.1 (0.8-1.4)

Weiderpass, 1999 6.2 (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? postmenopausal women (WHI)

Terapia ormonale sostitutiva e rischio oncologico

  • Breast cancer

  • Endometrial cancer

  • Ovarian cancer


HRT and risk of EOC postmenopausal women (WHI)

INCREASED INCIDENCE

NO YES

La Vecchia 1982 Cramer 1983

Smith 1984 Booth 1989

Wu 1988 Kaufman 1989

Hartge 1988 Whittemore 1993

Purdie 1999 Rodriquez 1995

Hempling 1997 Negri 1999

Coughlin 2000 Riman 2002

Sit 2002 Lacey 2002


HRT and EOC : Re-analysis of 4 European Studies postmenopausal women (WHI)

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


Cancer incidence and mortality in women receiving HRT postmenopausal women (WHI)

Population study: cohort of 22.597 Swedish Women.

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

SiteIncidence

O E RR 95% CI

Breast 634 643 1.0 0.9-1.1

Endometrium 261 147 1.8 1.6-2.0

Ovary 131 141 0.9 0.8-1.1

Colon 153 175 0.9 0.7-1.0

Liver and biliary tract 43 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


HRT and risk of EOC postmenopausal women (WHI)

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


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 cancer 1.58 (0.77-3.24)


HRT and risk of endometrioid EOC postmenopausal women (WHI)

Increased risk

YES NO

Weiss 1982Booth 1989

La Vecchia 1982Whittemore1992

Hunt 1987Hempling 1997

Purdie 1999


HRT and risk of EOC postmenopausal women (WHI)

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


HRT and risk of EOC postmenopausal women (WHI)

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


ERT and ovarian cancer postmenopausal women (WHI)mortality

Prospective study of 211.581 postmenopausal women

Death rates from ovarian cancer

ERT users RR (95% CI)

baseline users 1.51 (1.16-1.96)

former users 1.16 (0.99-1.37)

baseline users >10 years of use 2.20 (1.53-3.17)

former users > 10 years 1.59 (1.13-2.25)

Rodriquez 2001


Cancer incidence and mortality in women receiving HRT postmenopausal women (WHI)

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

Endometrium 25 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 - - - -


ERT/HRT and ovarian cancer postmenopausal women (WHI)mortality

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 use 1.6 (1.2-2.0)

ERT for 10 to 19 years 1.8 (1.1-3.0)

ERT >20 years 3.2 (1.7-5.7)

HRT after prior ERT 1.5 (0.91-2.4)

HRT only use 1.1 (0.64-1.7)

HRT only use for <2 years 1.6 (0.78-3.3)

HRT only use for >2 years 0.8 (0.35-1.8)


ERT/HRT and ovarian cancer postmenopausal women (WHI)mortality

Case-control study: 655 ovarian cancer patients

3899 controls (all 50-74 years)

Ovarian cancer OR (95% CI)

Ever ERT use 1.43 (1.02-2.00)

Ever sequential HRT 1.54 (1.15-2.05)

Ever continous HRT 1.02 (0.73-1.43)

Riman 2000


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

Syed 2001

normal immortalized cancer

LH, FSH

E2, E1

5-dihydrotestosterone

Testosterone

Progesterone low-dose

Progesterone high-dose


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


Conclusion: Breast cancer ovarian epithelial cells

  • 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.


Conclusion: Endometrial cancer ovarian epithelial cells

  • 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.


Conclusion: Ovarian cancer ovarian epithelial cells

  • 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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