Reproductive Factors and Risk of Ovarian Cancer

Abstract

Ovarian epithelial cancer (OEC) is the most lethal gynaecological malignancy and the sixth most common cancer among women in industrialised countries. This review summarises the current knowledge on the role of reproductive factors for the development of OEC. Recent studies have shown that OECs represent a diverse group of cancers. This is partly reflected in the results of epidemiological and clinical studies which have investigated the impact of various reproductive factors on the risk of developing OEC. Fewer ovulatory cycles, parity and lactation were found to decrease the risk for OEC, whereas the association between infertility and ovarian cancer has not yet been fully elucidated and further investigation is required. None of the proposed hypotheses on the development of ovarian cancer fully explains the epidemiological and clinical findings of the association between reproductive factors and OEC development. Further research is warranted which would focus more on the clinical and genetic diversity of OECs to obtain a better understanding of the pathogenesis.

Zusammenfassung

Das epitheliale Ovarialkarzinom ist das gynäkologische Malignom mit der höchsten Letalitätsrate und die sechsthäufigste Krebserkrankung der Frau in den Industrieländern. Diese Übersichtsarbeit fasst die aktuellen Kenntnisse zur Rolle reproduktiver Faktoren bei der Entwicklung von Ovarialkarzinomen zusammen. Aktuelle Studien zeigen, dass es sich bei Ovarialkarzinomen um heterogene Tumoren handelt. Dies wird teilweise auch in Resultaten epidemiologischer und klinischer Studien reflektiert, welche die verschiedenen Effekte reproduktiver Faktoren auf das Ovarialkarzinom untersuchten. Für eine kurze Lebensspanne mit menstruellen Zyklen, Parität und Laktation wurde eine negative Assoziation mit dem Ovarialkarzinomrisiko gezeigt, wohingegen der Zusammenhang zwischen Infertilität und Ovarialkarzinomen nicht gänzlich geklärt ist. Keine der bisher formulierten Hypothesen zur Entwicklung von Ovarialkarzinomen kann die epidemiologischen und klinischen Erkenntnisse zum Zusammenhang zwischen reproduktiven Faktoren und der Ovarialkarzinomentwicklung eindeutig erklären. Weitere wissenschaftliche Bemühungen sind erforderlich, die mehr Gewicht auf die genetische Vielfalt von Ovarialkarzinomen legen, damit ein detailliertes Verständnis ihrer Pathogenese erreicht werden kann.

Key words

reproductive factors - ovarian malignancy - parity - lactation - infertility - PCO syndrome

Schlüsselwörter

reproduktive Faktoren - Ovarmalignom - Parität - Laktation - Infertilität - PCO-Syndrom

• References

• 1 Jemal A, Bray F, Center MM et al. Global cancer statistics. CA Cancer J Clin 2011; 61: 69-90
• 2 Kurman RJ, Shih Ie M. Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer – shifting the paradigm. Hum Pathol 2011; 42: 918-931
• 3 Fathalla MF. Incessant ovulation – a factor in ovarian neoplasia?. Lancet 1971; 2: 163
• 4 Schildkraut JM, Bastos E, Berchuck A. Relationship between lifetime ovulatory cycles and overexpression of mutant p 53 in epithelial ovarian cancer. J Natl Cancer Inst 1997; 89: 932-938
• 5 Kuhn E, Kurman RJ, Shih IM. Ovarian cancer is an imported disease: fact or fiction?. Curr Obstet Gynecol Rep 2012; 1: 1-9
• 6 Przybycin CG, Kurman RJ, Ronnett BM et al. Are all pelvic (nonuterine) serous carcinomas of tubal origin?. Am J Surg Pathol 2010; 34: 1407-1416
• 7 Kuhn E, Kurman RJ, Vang R et al. TP53 mutations in serous tubal intraepithelial carcinoma and concurrent pelvic high-grade serous carcinoma – evidence supporting the clonal relationship of the two lesions. J Pathol 2012; 226: 421-426
• 8 Marquez RT, Baggerly KA, Patterson AP et al. Patterns of gene expression in different histotypes of epithelial ovarian cancer correlate with those in normal fallopian tube, endometrium, and colon. Clin Cancer Res 2005; 11: 6116-6126
• 9 Murdoch WJ, Martinchick JF. Oxidative damage to DNA of ovarian surface epithelial cells affected by ovulation: carcinogenic implication and chemoprevention. Exp Biol Med (Maywood) 2004; 229: 546-552
• 10 Cramer DW, Welch WR. Determinants of ovarian cancer risk. II. Inferences regarding pathogenesis. J Natl Cancer Inst 1983; 71: 717-721
• 11 Vanderhyden BC, Shaw TJ, Ethier JF. Animal models of ovarian cancer. Reprod Biol Endocrinol 2003; 1: 67
• 12 Blaakaer J, Baeksted M, Micic S et al. Gonadotropin-releasing hormone agonist suppression of ovarian tumorigenesis in mice of the Wx/Wv genotype. Biol Reprod 1995; 53: 775-779
• 13 Risch HA. Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone. J Natl Cancer Inst 1998; 90: 1774-1786
• 14 Silva EG, Tornos C, Fritsche jr. HA et al. The induction of benign epithelial neoplasms of the ovaries of guinea pigs by testosterone stimulation: a potential animal model. Mod Pathol 1997; 10: 879-883
• 15 Nishizuka Y, Sakakura T, Tsujimura T et al. Steroid biosynthesis in vitro by dysgenetic ovaries induced by neonatal thymectomy in mice. Endocrinology 1973; 93: 786-792
• 16 Helzlsouer KJ, Alberg AJ, Gordon GB et al. Serum gonadotropins and steroid hormones and the development of ovarian cancer. JAMA 1995; 274: 1926-1930
• 17 Wynder EL, Dodo H, Barber HR. Epidemiology of cancer of the ovary. Cancer 1969; 23: 352-370
• 18 Sonnichsen AC, Lindlacher U, Richter WO et al. [Obesity, body fat distribution and the incidence of breast, cervical, endometrial and ovarian carcinomas]. Dtsch Med Wochenschr 1990; 115: 1906-1910
• 19 [Anonym] Ovarian cancer and body size: individual participant meta-analysis including 25,157 women with ovarian cancer from 47 epidemiological studies. PLoS Med 2012; 9: e1001200
• 20 Olsen CM, Green AC, Nagle CM et al. Epithelial ovarian cancer: testing the ‘androgens hypothesis . Endocr Relat Cancer 2008; 15: 1061-1068
• 21 Kotsopoulos J, Baer HJ, Tworoger SS. Anthropometric measures and risk of epithelial ovarian cancer: results from the nursesʼ health study. Obesity (Silver Spring) 2010; 18: 1625-1631
• 22 Lahmann PH, Cust AE, Friedenreich CM et al. Anthropometric measures and epithelial ovarian cancer risk in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer 2010; 126: 2404-2415
• 23 Gong TT, Wu QJ, Vogtmann E et al. Age at menarche and risk of ovarian cancer: a meta-analysis of epidemiological studies. Int J Cancer 2013; 132: 2894-2900
• 24 Tsilidis KK, Allen NE, Key TJ et al. Oral contraceptive use and reproductive factors and risk of ovarian cancer in the European Prospective Investigation into Cancer and Nutrition. Br J Cancer 2011; 105: 1436-1442
• 25 Braem MG, Onland-Moret NC, van den Brandt PA et al. Reproductive and hormonal factors in association with ovarian cancer in the Netherlands cohort study. Am J Epidemiol 2010; 172: 1181-1189
• 26 Tung KH, Goodman MT, Wu AH et al. Reproductive factors and epithelial ovarian cancer risk by histologic type: a multiethnic case-control study. Am J Epidemiol 2003; 158: 629-638
• 27 Soegaard M, Jensen A, Hogdall E et al. Different risk factor profiles for mucinous and nonmucinous ovarian cancer: results from the Danish MALOVA study. Cancer Epidemiol Biomarkers Prev 2007; 16: 1160-1166
• 28 Whittemore AS, Harris R, Itnyre J. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Collaborative Ovarian Cancer Group. Am J Epidemiol 1992; 136: 1184-1203
• 29 Jordan SJ, Siskind V. C Green A et al. Breastfeeding and risk of epithelial ovarian cancer. Cancer Causes Control 2010; 21: 109-116
• 30 Gates MA, Rosner BA, Hecht JL et al. Risk factors for epithelial ovarian cancer by histologic subtype. Am J Epidemiol 2010; 171: 45-53
• 31 Titus-Ernstoff L, Perez K, Cramer DW et al. Menstrual and reproductive factors in relation to ovarian cancer risk. Br J Cancer 2001; 84: 714-721
• 32 Purdie DM, Siskind V, Bain CJ et al. Reproduction-related risk factors for mucinous and nonmucinous epithelial ovarian cancer. Am J Epidemiol 2001; 153: 860-864
• 33 McNeilly AS. Lactational control of reproduction. Reprod Fertil Dev 2001; 13: 583-590
• 34 Riman T, Dickman PW, Nilsson S et al. Risk factors for invasive epithelial ovarian cancer: results from a Swedish case-control study. Am J Epidemiol 2002; 156: 363-373
• 35 Merrill RM, Fugal S, Novilla LB et al. Cancer risk associated with early and late maternal age at first birth. Gynecol Oncol 2005; 96: 583-593
• 36 Risch HA, Marrett LD, Jain M et al. Differences in risk factors for epithelial ovarian cancer by histologic type. Results of a case-control study. Am J Epidemiol 1996; 144: 363-372
• 37 Kvale G, Heuch I, Nilssen S et al. Reproductive factors and risk of ovarian cancer: a prospective study. Int J Cancer 1988; 42: 246-251
• 38 Whiteman DC, Murphy MF, Cook LS et al. Multiple births and risk of epithelial ovarian cancer. J Natl Cancer Inst 2000; 92: 1172-1177
• 39 Kurian AW, Balise RR, McGuire V et al. Histologic types of epithelial ovarian cancer: have they different risk factors?. Gynecol Oncol 2005; 96: 520-530
• 40 Jordan SJ, Green AC, Nagle CM et al. Beyond parity: association of ovarian cancer with length of gestation and offspring characteristics. Am J Epidemiol 2009; 170: 607-614
• 41 Brinton LA, Melton 3rd LJ, Malkasian jr. GD et al. Cancer risk after evaluation for infertility. Am J Epidemiol 1989; 129: 712-722
• 42 Rodriguez C, Tatham LM, Calle EE et al. Infertility and risk of fatal ovarian cancer in a prospective cohort of US women. Cancer Causes Control 1998; 9: 645-651
• 43 Ness RB, Cramer DW, Goodman MT et al. Infertility, fertility drugs, and ovarian cancer: a pooled analysis of case-control studies. Am J Epidemiol 2002; 155: 217-224
• 44 Rossing MA, Tang MT, Flagg EW et al. A case-control study of ovarian cancer in relation to infertility and the use of ovulation-inducing drugs. Am J Epidemiol 2004; 160: 1070-1078
• 45 Jensen A, Sharif H, Olsen JH et al. Risk of breast cancer and gynecologic cancers in a large population of nearly 50,000 infertile Danish women. Am J Epidemiol 2008; 168: 49-57
• 46 Venn A, Watson L, Bruinsma F et al. Risk of cancer after use of fertility drugs with in-vitro fertilisation. Lancet 1999; 354: 1586-1590
• 47 Pearce CL, Templeman C, Rossing MA et al. Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies. Lancet Oncol 2012; 13: 385-394
• 48 Schildkraut JM, Schwingl PJ, Bastos E et al. Epithelial ovarian cancer risk among women with polycystic ovary syndrome. Obstet Gynecol 1996; 88: 554-559
• 49 Chittenden BG, Fullerton G, Maheshwari A et al. Polycystic ovary syndrome and the risk of gynaecological cancer: a systematic review. Reprod Biomed Online 2009; 19: 398-405
• 50 Pierpoint T, McKeigue PM, Isaacs AJ et al. Mortality of women with polycystic ovary syndrome at long-term follow-up. J Clin Epidemiol 1998; 51: 581-586
• 51 Brinton LA, Moghissi KS, Westhoff CL et al. Cancer risk among infertile women with androgen excess or menstrual disorders (including polycystic ovary syndrome). Fertil Steril 2010; 94: 1787-1792
• 52 Rebar R, Judd HL, Yen SS et al. Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome. J Clin Invest 1976; 57: 1320-1329
• 53 Baird DT, Corker CS, Davidson DW et al. Pituitary-ovarian relationships in polycystic ovary syndrome. J Clin Endocrinol Metab 1977; 45: 798-801
• 54 Rhiem K, Pfeifer K, Schmutzler RK et al. Risk-reducing surgery in women at risk for familial breast or ovarian cancer. Geburtsh Frauenheilk 2012; 72: 833-839
• 55 Waldmann A, Eisemann N, Katalinic A. Epidemiology of malignant cervical, corpus uteri and ovarian tumours – current data and epidemiological trends. Geburtsh Frauenheilk 2013; 73: 123-129
• 56 Bolton KL, Ganda C, Berchuck A et al. Role of common genetic variants in ovarian cancer susceptibility and outcome: progress to date from the Ovarian Cancer Association Consortium (OCAC). J Intern Med 2012; 271: 366-378
• 57 Larson NB, Jenkins GD, Larson MC et al. Kernel canonical correlation analysis for assessing gene-gene interactions and application to ovarian cancer. Eur J Hum Genet 2013;
• 58 Cicek MS, Koestler DC, Fridley BL et al. Epigenome-wide ovarian cancer analysis identifies a methylation profile differentiating clear-cell histology with epigenetic silencing of the HERG K+ channel. Hum Mol Genet 2013; [Epub ahead of print]
• 59 Pharoah PD, Tsai YY, Ramus SJ et al. GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer. Nat Genet 2013; 45: 362-370
• 60 Bojesen SE, Pooley KA, Johnatty SE et al. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer. Nat Genet 2013; 45: 371-384
• 61 Fasching PA, Gayther S, Pearce L et al. OCAC (Ovarian Cancer Association Consortium). Role of genetic polymorphisms and ovarian cancer susceptibility. Mol Oncol 2009; 3: 171-181
• 62 [Anonym] Integrated genomic analyses of ovarian carcinoma. Nature 2011; 474: 609-615