Academic dissertation

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Table of contents List of original publications Abbreviations Abstract Introduction Review of the literature Aims of the study Subjects and methods 4

Results Discussion Conclusions Acknowledgements References Original publications 5

List of original publications 6

Abbreviations 7

Abstract Background Subjects and methods 8

Results Conclusions 9

Introduction 10

Review of the literature Ovaries Figure 1. Illustration of anatomical parts of ovary and fallopian tube. 12

Ovarian cancer Table 1. Features and mutations associated with different histological types of epithelial ovarian cancers. Modified according to reviews by Fleming 2006, and Jayson et al. 2014. High-grade serous Low-grade serous Endometroid (high- and lowgrade) Clear cell Mucinous Possible origin Fimbriae of fallopian tubes Benign cysts or borderline ovarian tumors Endometrium/ endometriosis Endometrium/ endometriosis Benign cysts or borderline ovarian tumors Behaviour Aggressive Indolent Depend on grade Aggressive Indolent Sensitivity to chemotherapy sensitive less sensitive less sensitive non-sensitive less sensitive Some typical gene mutations TP53, BRCA1/2 KRAS, BRAF ARID1A, P13KCA, PTEN ARID1A, P13KCA, PTEN KRAS, ERBB2 amplifications Incidence 13

Theories on etiology 15

Genetic predisposition 18

Protective and risk factors 19

Table 2. Factors associated with ovarian cancer. A relative risk <1 means protective effect and relative risk >1 means increased risk. Modified from the studies by Annegers et al. 1979, Booth et al. 1989, Risch et al. 1994, 1996, Auranen et al. 1996, Ness et al. 2002, Hinkula et al. 2006, Beral et al. 2008, a review by Sueblinvong and Carney 2009, Domcheck et al. 2010, and meta-analyses by Cibula et al. 2010 and Rice et al. 2012. Factor Relative risk Parity 0.3-0.7 Oral contraceptive use 0.3-0.6 Hysterectomy 0.5-0.9 Tubal ligation 0.2-0.8 Breast feeding 0.6-0.9 Family history of ovarian cancer 2.0-4.0 BRCA 1/2 mutations 20-30 Infertility 2.0-3.0 Table 3. Risk and protective factors for four main histological types of ovarian cancer. risk increase, risk decrease, no effect. Modified according to the studies of Risch et al. 1996, Kurian et al. 2005, Nagle et al. 2008, Gates et al. 2010 and Yang et al. 2012. Risk factors Serous Endometroid Mucinous Clear cell Parity Oral contraceptive use Hysterectomy Tubal ligation Endometriosis Tobacco smoking Body mass index >25 kg/m 2 Breastfeeding 20

Diagnosis Management and survival 21

Fallopian tubes 23

Primary fallopian tube carcinoma Incidence Protective and risk factors 25

Table 4. Possible protective and risk factors for primary fallopian tube carcinoma (PFTC). Modified according to studies of Riska et al. 2007a, Jordan et al. 2008 and a review by Kalampokas et al. 2013. Factor Impact on PFTC risk Parity Protective Oral contraceptive use Protective Tubal ligation Protective Chronic tubal inflammation Risk increasing BRCA-mutations Risk increasing Infertility Risk increasing Diagnosis, management and survival 26

Menopause Immediate symptoms Long-term consequences 28

Postmenopausal hormone therapies Estrogen therapy 29

Table 5. Type, mode and route of administration and daily dose of estrogen in regimens used in Finland since 1994. Regimen Administration Daily dose (mg) Estradiol Oral 1, 2 Transdermal patch 0.025-0.1 Transdermal gel 0.5, 1, 0.6-1 Vaginal tablet 0.001-0.0025 Vaginal ring 0.025 Estriol Vaginal suppository 0.5 Vaginal creme 0.1-1 30

Progestins and estrogen-progestin therapies Table 6. The binding of different progestins and tibolone metabolites to various steroid receptors. Modified according to reviews by Kuhl 2005 and Stanczyk 2013, based mainly on animal studies. ++ strong effect, + effect, (+) weak effect, - no effect,? effect is unknown. The progestins used in Finland are included. Progestin Antiestrogenic Estrogenic Androgenic Antiandrogenic Glucocor- Antiminera ticoid locorticoid Progesterone + - - (+) + + Cyproterone acetate + - - + + - Medroxyprogesterone acetate + - (+) - + + Medrogestone + - - -? - Dydrogesterone + - - -? (+) Norethisterone + + + - - - Levonorgestrel + - + - - - Gestodene + - + - (+) + Norgestimate + - + -?? Δ4 tibolone + + ++ - - - Drospirenone + - - + - + Trimegestrone + - - (+) - (+) Promegestrone + - - - + - Nomegestrol acetate + - - + - - 31

Table 7. Type, mode, daily dose and route of administration of progestins used in combination with estradiol in postmenopausal hormone regimens in Finland since 1994. Progestin regimen Administration Daily dose (mg) Sequential, Oral norethisterone acetate oral 1 medroxyprogesterone acetate oral 10, 20 levonorgestrel oral 0.25 dydrogesterone oral 10, 20 medroxyprogesterone oral 5, 10 megesterole acetate oral 10 trimegesterone oral 2 progesterone oral 100-200 lynesterol oral 5 trimegesterone oral 0.5 Sequential, Transdermal norethisterone acetate patch 0.17, 025 levonorgestrel patch 0.01, 0.02 Continuous, Oral norethisterone acetate oral 0.5, 0.7, 1 medroxyprogesterone acetate oral 2.5, 5 dydrogesterone oral 5 drospirenone oral 2 Continuous, Transdermal norethisterone acetate patch 0.17, 0.25 Continuous, Intrauterine levonorgestrel intrauterine system 0.02 Levonorgestrel-releasing intrauterine system 32

Tibolone Others 33

Effects of postmenopausal hormone therapy Benefits 34

Adverse effects Influence of administration routes 35

Postmenopausal hormone therapy and general risk of cancer 36

Hormone therapy and ovarian cancer Hormone therapy and primary fallopian tube carcinoma 37

Table 11. Some studies on ovarian cancer risk in users of postmenopausal hormone therapy (HT) (estrogen-only therapy, ET or estrogen-progestin therapy, EPT). RR, risk ratio; OR, odds ratio; CI, confidence interval. * All relative risks are for HT use 5 years if not marked otherwise. * Only randomized placebo-controlled trial ** Published after the initiation of my thesis. Study Design Years conducted Study population/ number of subjects Regimen Relative risk by RR, or and 95% CI for HT use 5 years* Cramer et al. 1983 Case-control 1978-1981 173/173 ET OR for ET 2.83 (0.87-9.26) (cases/controls) Lee et al. 1986 Case-control 1980-1983 160/1,210 ET OR for ET use 6 years 1.7 (0.8-3.6) (cases/controls) Hartge et al. 1988 Cohort 1978-1981 203/244 ET RR for ET use >2.5 years 0.4 (0.2-0.7) (cases/controls) Booth et al. 1989 Case-control 1978-1983 235/451 ET OR for ever-use of ET 1.5 (0.9-2.6) (cases/controls) Whittemore et al. 1992 Case-control 1956-1986 2,197/8,893 ET RR for ET 1.0 (0.58-1.80) (cases/controls) Parazzini et al. 1994 Case-control 1980-1992 953/2,503 ET OR for ET use 2 years 1.7 (0.9-3.4) (cases/controls) Risch et al. 1996 Case-control 1989-1992 Hempling et al. 1997 Case-control 1982-1995 Purdie et al. 1999 Case-control 1990-1993 Lacey et al. 2002 Cohort 1979-1998 Riman et al. 2002 Case-control 1993-1995 Anderson et al. 2003* Randomized trial 1993-1998 Pike et al. 2004 Case-control 1992-1998 Moorman et al. 2005 Case-control 1999-2003 Lacey et al. 2006 Cohort 1995-2000 Danforth et al. 2007 Cohort 1978-2002 Beral et al. 2007 Cohort 1996-2004 Rossing et al. 2007 Case-control 2002-2005 Mørch et al. 2009** Cohort 1995-2005 Hildebrand et al. 2010** Cohort 1992-2007 Tsilidis et al. 2011** Cohort 1992-2000 Trabert et al. 2012** Cohort 1996-2006 367/564 (cases/controls) 491/741 (cases/controls) 732/784 (cases/controls) 233/44,241 (cancers/cohort) 655/3,899 (cases/controls) 32/16,608 (cancers/cohort) 477/660 (cases/controls) 364/370 (cases/controls) 214/97,638 (cancers/cohort) 389/82,905 (cancers/cohort) 2,273/287,143 (cancers/cohort of current users) ET and EPT HT not specified ET and EPT OR for any HT 1.05 (1.01-1.09) only nonmucinous tumors included OR for HT 5 years 0.6 (0.3-1.1) OR for ET 0.94 (0.67-1.30) OR for EPT >3years of use 1.33 (0.88-2.00) RR for ET 1.20 (1.10-1.32) RR for EPT 0.93 (0.25-3.41) OR for ever-use of ET 1.43 (1.02-2.00) OR for ever-use of EPT 1.54 (1.15-2.05) ET and EPT ET and EPT EPT RR for EPT 2.42 (0.64-9.12) ET and EPT ET and EPT ET and EPT ET and EPT ET, EPT and tibolone 299/614 (cases/controls) ET and EPT 2,681/909,946 (epithelial ET and ovarian cancers/cohort) EPT 297/ 22,721 (cancers/cohort of everand current users) 424/37,630 (cancers/cohort of current users) 426/50,397 (cancers/cohort of current users) ET and EPT ET, EPT and Tibolone ET and EPT OR for ET 1.13 (0.97-1.31) OR for EPT 1.00 (0.80-1.25) OR for ET use of 5 years 1.5 (0.6-3.5) and 10 years 2.2 (1.2-4.1) OR for EPT use of 5 year 1.1 (0.5-2.6) and 10 years 1.0 (0.5-2.0) RR for ET 1.33 (0.89-2.00) RR for sequential EPT 3.09 (1.68-5.68) and RR for continuous EPT 1.82 (1.03-3.23) RR for ET 1.25 (1.12-1.38) RR for EPT 1.04 (0.82-1.32) RR for ET 1.53 (1.27-1.84) RR for EPT 1.17 (1.02-1.34) RR for tibolone 1.07 (0.81-1.41) OR for ET 1.4 (0.7-2.6) OR for EPT 1.00 (0.60-1.50) RR for ET 1.31 (1.11-1.54) RR for EPT 1.50 (1.34-1.68) RRs for any duration RR for ET 1-<10 years 1.70 (1.02-2.83) RR for EPT 5 years 1.30 (0.81-2.08) RR for ever-use of ET 1.63 (1.08-2.47) RR for ever-use of EPT 1.20 (0.89-1.94) RR for ever-use of tibolone 2.19 (1.06-4.50) RR for ET 10 years 2.15 (1.30-3.57) RR for EPT 10 years 1.68 (1.13-2.49) 38

Aims of the study 39

Subjects and methods Permissions Registers used in the studies 40

Table 12. The nation-wide registers employed in the studies I-IV. Register Register Keeper Used in Studies Medical reimbursement National Social register Insurance Institution Cancer Registry Institute for Health and Welfare Hospital care register Institute for Health and Welfare Finnish population register Population Register Centre Sterilization register Institute for Health and Welfare Complete nationwide data available from I, II, III, IV 1994- I, II, III, IV 1953- I, II, III, IV 1986- II, IV 1972- IV 1975- Study populations Cohort studies 41

Case-control studies 43

Use of hormone therapy Cohort studies Case-control-studies 44

Statistical methods Cohort studies 45

Case-control studies Table 13. The study populations, design, follow-up, hormone therapies and registers used in the studies I-IV. Study Design Study Period Subjects Follow-up Hormone therapies Cencoring event (Excluded) Registers used I Cohort 1994-2006 224,015 women 602 incident ovarian cancers 1994-2006, 1,591,201 women-years mean follow-up 7 years EPT Hysterectomy n=23,371 Cancer registry, Medical reimbursement register, Patient care register III Cohort 1994-2008 365,601 women 160 incident PFTCs 1994-2008, 1,0009,358 womenyears (ET-users), 2,145,659 women-years (EPT-users) mean follow-up 9 years in both groups ET, EPT Salpingectomy n=18,310 Cancer registry, Medical reimbursement register, Patient care register II Casecontrol 1994-2007 3,958 ovarian cancer cases 11,325 controls 1995-2007 ET, EPT, E+LNG- IUS, tibolone Oophorectomy n=506 Cancer registry, Medical reimbursement register, Patient care register, Population register IV Casecontrol 1994-2007 360 PFTC cases 3,442 controls 1995-2007 ET, EPT, E+LNG- IUS, tibolone Salpingectomy n=158 Cancer Registry, Medical reimbursement register, Patient care register, Population register, Sterilization register 46

Results Features of hormone therapy use 47

Ovarian cancer risk Cohort study (study I) Table 14. Ovarian cancer risk in estradiol-progestin therapy (EPT) users during 1994-2006 (study I). SIR, Standardized incidence ratio; CI confidence interval. EPT Observed Expexted SIR 95% CI >6 months<5 years 149 158 0.94 0.80-1.10 5years 239 197 1.21 1.06-1.37 10years 27 24 1.13 0.74-1.64 Ever-use of EPT 602 549 1.10 1.01-1.18 Table 15. Ovarian cancer risk in users of sequential and continuous estradiol-progestin therapy (EPT) (study I). SIR, Standardized incidence ratio; CI confidence interval. EPT Observed Expected SIR 95% CI Sequential <5 years 100 101 0.99 0.80-1.19 Continuous <5years 30 35 0.85 0.59-1.18 Sequential 5years 85 61 1.39 1.11-1.72 Continuous 5years 24 19 1.27 0.81-1.88 48

Table 16. Ovarian cancer risk in users of medroxyprogesterone acetate (MPA) and norethisterone acetate (NETA) as parts of estradiol-progestin therapy (EPT ), (study I). SIR, Standardized incidence ratio; CI confidence interval. Progestin and duration Observed Expected SIR 95% CI MPA <5years 48 57 0.84 0.62-1.11 MPA 5years 52 41 1.26 0.94-1.64 NETA <5years 73 78 0.93 0.73-1.17 NETA 5years 75 53 1.42 1.11-1.77 Case-control study (study II) 49

Table 17. Risk of ovarian cancer, the type of postmenopausal hormone therapy (HT) and duration of exposure. A woman may be included in more than one category of hormone therapy. Adjusted for parity, age at births of children and hysterectomy (study II). ET, estradiol-only therapy; EPT, estradiol-progestin therapy; OR, odds ratio; CI, confidence interval; LNG-IUS, levonorgestrel-releasing intrauterine system. Hormone therapy and duration Cases Controls OR 95% CI p-value ET <1 year 98 290 1.05 0.83-1.33 0.674 ET 1-5 years 146 493 0.93 0.76-1.13 0.443 ET >5 years 312 829 1.15 0.99-1.32 0.061 P-value for trend = 0.158 EPT sequential <1 year 78 251 0.88 0.68-1.14 0.338 EPT sequential 1-5 years 181 488 1.03 0.86-1.25 0.727 EPT sequential >5 years 196 424 1.35 1.12-1.63 0.002 P-value for trend = 0.011 EPT continuous <1 year 153 413 0.98 0.81-1.20 0.871 EPT continuous 1-5 years 166 413 1.05 0.86-1.28 0.625 EPT continuous >5 years 33 68 1.19 0.77-1.85 0.430 P-value for trend = 0.499 estradiol+ LNG-IUS 5 years 4 12 0.92 0.29-2.87 0.885 estradiol+ LNG-IUS >5 years 23 64 1.02 0.63-1.66 0.929 tibolone <1 year 33 101 0.86 0.58-1.29 0.464 tibolone >1 year 27 72 1.01 0.64-1.60 0.963 unspecified type of HT <5 years 7 20 1.04 0.43-2.49 0.935 unspecified type of HT 5-10 years 9 19 1.31 0.57-2.99 0.520 unspecified type of HT >10 years 12 15 2.33 1.04-5.19 0.039 P-value for trend = 0.034 50

Table 18. Risk of ovarian cancer by histological type, the type of postmenopausal hormone therapy and duration of exposure. A woman may be included in more than one category of hormone therapy. Adjusted for parity, age at births of children and hysterectomy (study II). ET, estradiol-only therapy; EPT, estradiolprogestin therapy; OR, odds ratio; CI, confidence interval. Histology and hormone therapy Cases Controls OR 95% CI p-value Serous (48%) 1,903 5,430 ET <1year 53 133 1.26 0.91-1.76 0.164 ET 1-5 years 89 242 1.15 0.89-1.49 0.291 ET >5 years 201 431 1.45 1.20-1.75 <0.0001 P-value for trend <0.0001 EPT sequential <1 year 38 116 1.03 0.70-1.50 0.887 EPT sequential 1-5 years 105 219 1.40 1.08-1.82 0.011 EPT sequential >5 years 99 225 1.32 1.01-1.71 0.039 P-value for trend =0.004 EPT continuous <1 year 92 217 1.09 0.84-1.43 0.513 EPT continuous 1-5 years 100 216 1.16 0.88-1.52 0.290 EPT continuous >5years 19 38 1.18 0.67-2.10 0.566 P-value for trend =0.218 Endometroid (19%) 748 2,153 ET <1 year 17 46 1.19 0.67-2.11 0.552 ET 1-5 years 23 83 0.98 0.59-1.63 0.938 ET >5 years 53 141 1.25 0.88-1.76 0.209 P-value for trend =0.248 EPT Sequential <1 year 17 57 0.78 0.44-1.38 0.392 EPT Sequential 1-5 years 34 100 0.91 0.59-1.41 0.685 EPT Sequential >5 years 46 76 1.88 1.24-2.86 0.003 P-value for trend =0.041 EPT continuous <1 year 33 72 1.17 0.74-1.85 0.499 EPT continuous 1-5 years 35 65 1.43 0.90-2.26 0.131 EPT continuous >5 years 5 9 1.93 0.59-6.28 0.277 P-value for trend =0.062 Mucinous (11%) 417 1,194 ET <1 year 3 38 0.24 0.07-0.80 0.021 ET 1-5 years 10 67 0.45 0.22-0.91 0.026 ET >5 years 12 82 0.35 0.19-0.67 0.002 P-value for trend <0.001 EPT Sequential <1 year 7 31 0.62 0.26-1.45 0.268 EPT Sequential 1-5 years 17 54 0.96 0.51-1.80 0.908 EPT Sequential >5 years 9 45 0.57 0.26-1.25 0.161 P-value for trend =0.172 EPT continuous <1 year 10 51 0.56 0.27-1.15 0.113 EPT continuous 1-5 years 8 53 0.45 0.20-1.00 0.053 EPT continuous >5 years 2 8 0.82 0.14-4.71 0.822 P-value for trend =0.03 Clear Cell (4%) 155 441 ET <1 year 3 13 0.68 0.16-2.94 0.602 ET 1-5 years 2 32 0.12 0.02-0.87 0.035 ET >5 years 5 24 0.72 0.23-2.29 0.578 P-value for trend =0.087 EPT Sequential <1 year 5 16 0.61 0.18-2.03 0.421 51

EPT Sequential 1-5 years 8 27 0.46 0.17-1.28 0.137 EPT Sequential >5 years 9 19 1.71 0.67-4.40 0.265 P-value for trend =0.928 EPT continuous <1 year 3 14 0.62 0.16-2.38 0.484 EPT continuous 1-5 years 4 18 0.56 0.14-2.20 0.405 EPT continuous >5 years 1 6 0.21 0.02-2.48 0.216 P-value for trend =0.149 Other (18%) 735 2,107 ET <1 year 22 60 1.08 0.65-1.80 0.773 ET 1-5 years 22 69 0.95 0.58-1.57 0.845 ET >5 years 41 151 0.82 0.56-1.20 0.307 P-value for trend =0.305 EPT Sequential <1 year 11 31 0.89 0.43-1.82 0.747 EPT Sequential 1-5 years 17 88 0.50 0.29-0.88 0.017 EPT Sequential >5 years 33 59 1.65 1.02-2.65 0.041 P-value for trend =0.400 EPT continuous <1 year 15 59 0.66 0.36-1.21 0.184 EPT continuous 1-5 years 19 61 0.86 0.49-1.52 0.607 EPT continuous > 5 years 6 7 1.45 0.42-4.97 0.557 P-value for trend =0.577 52

Primary fallopian tube carcinoma risk Cohort study (study III) Table 19. Primary fallopian tube carcinoma (PFTC) risk in users of hormone therapy during 1994-2008 (study III). ET, estradiol-only therapy; EPT, estradiol-progestin therapy; SIR, Standardized incidence ratio; CI confidence interval. ET Observed Expected SIR 95% CI >6 months<5 years 9 12 0.77 0.35-1.45 5years 11 11 1.01 0.50-1.80 10years 3 3 1.08 0.22-3.14 Ever-Use of ET 34 36 0.95 0.66-1.32 EPT Observed Expected SIR 95% CI >6 months<5 years 24 20 1.19 0.76-1.77 5years 67 31 2.15 1.66-2.72 10years 19 6 3.36 2.02-5.24 Ever-Use of EPT 126 71 1.77 1.47-2.08 53

Table 20. Primary fallopian tube carcinoma risk in users of sequential and continuous estradiol-progestin therapy (EPT) and medroxyprogesterone acetate (MPA) and norethisterone acetate (NETA) as parts of EPT (study III). SIR, Standardized incidence ratio; CI confidence interval. EPT Observed Expected SIR 95% CI Sequential <5 years 16 8 1.51 0.87-2.46 Sequential 5years 23 8 3.05 1.93-4.57 Continuous <5 years 2 5 0.38 0.05-1.37 Continuous 5years 2 3 0.70 0.08-2.51 MPA <5 years 12 6 1.85 0.96-3.23 MPA 5years 20 6 3.34 2.24-5.15 MPA 10years 3 1 4.52 0.93-13.2 NETA <5 years 6 10 0.63 0.23-1.36 NETA 5years 15 8 1.93 1.08-3.17 NETA 10years 5 1 4.36 1.42-10.18 Case-control study (study IV) 54

Table 21. Risk of primary fallopian tube carcinoma according to the type and duration of postmenopausal hormone therapy. A woman may be included in more than one category of hormone therapy. Adjusted for parity, age at last delivery, hysterectomy and sterilization (study IV). ET, estradiol-only therapy; EPT, estradiol-progestin therapy; LNG- IUS, levonorgestrel-releasing intrauterine system; OR, odds ratio; CI confidence interval. Hormone therapy and duration Cases Controls OR 95% CI p-value ET <1 year 9 87 1.12 0.55-2.28 0.760 ET 1-5 years 19 141 1.51 0.90-2.53 0.122 ET >5 years 32 251 1.45 0.96-2.17 0.074 P-value for trend =0.1847 EPT sequential <1 year 11 79 1.35 0.69-2.66 0.384 EPT sequential 1-5 years 20 168 1.14 0.68-1.93 0.618 EPT sequential >5 years 43 135 3.37 2.23-5.08 <0.0001 P-value for trend <0.0001 EPT continuous <1 year 26 138 1.52 0.95-2.46 0.084 EPT continuous 1-5 years 24 125 1.63 1.00-2.67 0.052 EPT continuous >5 years 5 22 2.19 0.79-6.02 0.131 P-value for trend =0.074 estradiol+ LNG-IUS 5 years 0 4 NA NA 0.986 estradiol+ LNG-IUS >5 years 6 20 2.84 1.10-7.38 0.032 P-value for trend =0.088 tibolone <1 year 5 29 1.15 0.43-3.11 0.781 tibolone >1 year 5 21 1.56 0.55-4.41 0.400 P-value for trend =0.6993 55

Other factors Table 22. Ovarian cancer risk according to parity, age at births and hysterectomy. Adjusted for HT use (study II). OR, odds ratio; CI confidence interval. Parity and age at first and last birth Cases Controls OR 95% CI p-value nulliparity reference 1 2 children, first birth <25, last birth <35 1,017 2,809 0.83 0.74-0.92 0.001 1 2 children, first birth <25, last birth 35 22 76 0.63 0.39-1.02 0.062 1 2 children, first birth 25, last birth <35 786 2,188 0.82 0.73-0.92 0.001 1 2 children, first birth 25, last birth 35 183 651 0.65 0.54-0.78 <0.001 3+ children, first birth <25, last birth <35 581 1,857 0.71 0.62-0.80 <0.001 3+ children, first birth <25, last birth 35 205 699 0.67 0.56-0.80 <0.001 3+ children, first birth 25, last birth <35 121 463 0.60 0.48-0.74 <0.001 3+ children, first birth 25, last birth 35 181 613 0.69 0.57-0.83 <0.001 Hysterectomy 245 943 0.71 0.61-0.82 <0.001 Table 23. Risk of Primary fallopian tube carcinoma according to parity, age at last delivery, hysterectomy and sterilization. Adjusted for hormone therapy use (study IV). OR, odds ratio; CI confidence interval. Parity and age at last delivery Cases Controls OR 95% CI p-value Nulliparity 77 635 reference 1-3 children, age at last delivery <35 217 1902 0.91 0.68-1.20 0.495 1-3 children age at last delivery 35 43 380 0.96 0.64-1.43 0.838 4+ children, age at last delivery <35 15 268 0.48 0.27-0.86 0.014 4+ children age at last delivery 35 8 257 0.26 0.12-0.55 <0.0001 Hysterectomy 19 198 0.93 0.61-1.43 0.732 Sterilization 29 281 0.88 0.52-1.49 0.803 56

Discussion 57

Conclusions 64

Acknowledgements 65

References 67

74:391-2. 69

Original publications 83