Abstract
Objective: Over the past decades the use of fertility drugs (FDs) has greatly increased. Recently, the possible association between the use of FDs and risk of cancer has aroused great concern. In this paper, we critically review the available epidemiologic studies.
Methods: We identified papers published between 1966 and 1999 that examined FDs and specific causes of subfertility in relation to the risks of cancers of the ovary, breast, endometrium and thyroid, and melanoma.
Results: Although present insights into the pathogenesis of hormone-related malignancies suggest a possible association between the use of FDs and the risk of specific cancers, this has not been convincingly demonstrated in epidemiologic studies. With regard to cancer risk in relation to the cause of subfertility, the only consistent association observed is an increased risk of endometrial cancer for women with subfertility due to hormonal disorders. While positive findings in some studies on FDs and ovarian cancer risk have aroused serious concern, the associations observed in most of these reports appear to be due to bias or chance rather than being causal. The most important sources of bias are inadequate confounder control for both parity and causes of subfertility.
Conclusions: To discriminate between the possible carcinogenic effects of various ovulation induction regimens, subfertility disorders, and reproductive characteristics associated with subfertility, future studies should include large populations of subfertile women with sufficient follow-up time. In such cohort studies the cause of subfertility should be measured adequately (based on medical records) and information about reproductive characteristics should be collected for all cohort members. Such studies should also include a group of subfertile women with an indication for FD use but not so treated.
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Chandra A, Stephen EH (1998) Impaired fecundity in the United States: 1982–1995. Fam Plann Perspect 30: 34–42.
Beurskens MP, Maas JW, Evers JL (1995) Subfertility in South Limburg: calculation of incidence and appeal for specialist care. [Dutch]. Ned Tijdschr Geneeskd 139: 235–238.
Wysowski DK (1993) Use of fertility drugs in the United States, 1973 through 1991. Fertil Steril 60: 1096–1098.
Merkus JMWM (1991) Meerlingen en artificiele voortplanting (Abstract). Symposium: Meerlingen; de epidemie van de jaren negentig in de obstetrie.
de Jong-van den Berg LTW, Cornel MC, van den Berg PB, et al. (1992) Ovulation-inducing drugs: a drug utilization and risk study in the Dutch population. Int J Risk Safety Med 3: 99–112.
Shu XO, Brinton LA, Gao YT, Yuan JM (1989) Population-based case-control study of ovarian cancer in Shanghai. Cancer Res 49: 3670–3674.
Whittemore AS, Harris R, Itnyre J (1992) 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 136: 1184–1203.
Franceschi S, La Vecchia C, Negri E, et al. (1994) Fertility drugs and risk of epithelial ovarian cancer in Italy. Hum Reprod 9: 1673–1675.
Shushan A, Paltiel O, Iscovich J, Elchalal U, Peretz T, Schenker JG (1996) Human menopausal gonadotropin and the risk of epithelial ovarian cancer. Fertil Steril 65: 13–18.
Parazzini F, Negri E, La Vecchia C, Moroni S, Franceschi S, Crosignani PG (1997) Treatment for infertility and risk of invasive epithelial ovarian cancer. Hum Reprod 12: 2159–2161.
Mosgaard BJ, Lidegaard O, Kjaer SK, Schou G, Andersen AN (1997) Infertility, fertility drugs, and invasive ovarian cancer: a case-control study. Fertil Steril 67: 1005–1012.
Ron E, Lunenfeld B, Menczer J, et al. (1987) Cancer incidence in a cohort of infertile women. Am J Epidemiol 125: 780–790.
Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG (1994) Ovarian tumors in a cohort of infertile women. N Engl J Med 331: 771–776.
Venn A, Watson L, Lumley J, Giles G, King C, Healy D (1995) Breast and ovarian cancer incidence after infertility and in vitro fertilisation. Lancet 346: 995–1000.
Modan B, Ron E, Lerner-Geva L, et al. (1998) Cancer incidence in a cohort of infertile women. Am J Epidemiol 147: 1038–1042.
Harris R, Whittemore AS, Itnyre J (1992) Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. III. Epithelial tumors of low malignant potential in white women. Collaborative Ovarian Cancer Group. Am J Epidemiol 136: 1204–1211.
Parazzini F, Negri E, La Vecchia C, et al. (1998) Treatment for fertility and risk of ovarian tumors of borderline malignancy. Gynecol Oncol 68: 226–228.
Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG (1996) Risk of breast cancer in a cohort in infertile women. Gynecol Oncol 60: 3–7.
Braga C, Negri E, La Vecchia C, Parazzini F, Dal Maso L, Franceschi S (1996) Fertility treatment and risk of breast cancer. Hum Reprod 11: 300–303.
Potashnik G, Lerner-Geva L, Genkin L, Chetrit A, Lunenfeld E, Porath A (1999) Fertility drugs and the risk of breast and ovarian cancers: results of a long-term follow-up study. Fertil Steril 71: 853–859.
Venn A, Watson L, Bruinsma F, Giles G, Healy D (1999) Risk of cancer after use of fertility drugs with in-vitro fertilisation. Lancet 354: 1586–1590.
Bernstein L, Ross RK, Henderson BE (1992) Relationship of hormone use to cancer risk. J Natl Cancer Inst Monogr 12: 137–147.
Schildkraut JM, Schwingl PJ, Bastos E, Evano. A, Hughes C (1996) Epithelial ovarian cancer risk among women with polycystic ovary syndrome. Obstet Gynecol 88: 554–559.
Brinton LA, Melton LJ, Malkasian GD Jr, Bond A, Hoover R (1989) Cancer risk after evaluation for infertility. Am J Epidemiol 129: 712–722.
Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG (1995) Risk of cutaneous melanoma in a cohort of infertile women. Melanoma Res 5: 123–127.
Brinton LA, Gridley G, Persson I, Baron J, Bergqvist A (1997) Cancer risk after a hospital discharge diagnosis of endometriosis. Am J Obstet Gynecol 176: 572–579.
Rodriguez C, Tatham LM, Calle EE, Thun MJ, Jacobs EJ, Heath CW Jr (1998) Infertility and risk of fatal ovarian cancer in a prospective cohort of US women. Cancer Causes Control 9: 645–651.
Le MG, Bachelot A, Hill C (1989) Characteristics of reproductive life and risk of breast cancer in a case-control study of young nulliparous women. J Clin Epidemiol 42: 1227–1233.
Gammon MD, Thompson WD (1990) Infertility and breast cancer: a population-based case-control study. Am J Epidemiol 132: 708–716.
Moseson M, Koenig KL, Shore RE, Pasternack BS (1993) The influence of medical conditions associated with hormones on the risk of breast cancer. Int J Epidemiol 22: 1000–1009.
Cowan LD, Gordis L, Tonascia JA, Jones GS (1981) Breast cancer incidence in women with a history of progesterone deficiency. Am J Epidemiol 114: 209–217.
Coulam CB, Annegers JF, Kranz JS (1983) Chronic anovulation syndrome and associated neoplasia. Obstet Gynecol 61: 403–407.
Garland M, Hunter DJ, Colditz GA, et al. (1998) Menstrual cycle characteristics and history of ovulatory infertility in relation to breast cancer risk in a large cohort of US women. Am J Epidemiol 147: 636–643.
Escobedo LG, Lee NC, Peterson HB, Wingo PA (1991) Infertility-associated endometrial cancer risk may be limited to specific subgroups of infertile women. Obstet Gynecol 77: 124–128.
Riman T, Persson I, Nilsson S (1998) Hormonal aspects of epithelial ovarian cancer: review of epidemiological evidence. Clin Endocrinol 49: 695–707.
Artini PG, Fasciani A, Cela V, et al. (1997) Fertility drugs and ovarian cancer. Gynecol Endocrinol 11: 59–68.
Tarlatzis BC, Grimbizis G, Bontis J, Mantalenakis S (1995) Ovarian stimulation and ovarian tumours: a critical reappraisal. Hum Reprod Update 1: 284–301.
Beltsos AN, Odem RR (1996) Ovulation induction and ovarian malignancy. Semin Reprod Endocrinol 14: 367–374.
Kaufman SC, Spirtas R, Alexander NJ (1995) Do fertility drugs cause ovarian tumors? J Women Health 4: 247–259.
Bristow RE, Karlan BY (1996) The risk of ovarian cancer after treatment for infertility. Curr Opin Obstet Gynecol 8: 32–37.
Burger CW, Kenemans P, Schoemaker J (1996) Ovarian hyper-stimulation: a risk factor for granulosa cell tumour of the ovary? CME J Gynecol Oncol 132–135.
Bristow RE, Karlan BY (1996) Ovulation induction, infertility, and ovarian cancer risk. Fertil Steril 66: 499–507.
Lely C, Burger CW (1996) Fertility drugs and in vitro fertilisation and the risk of ovarian cancer. Oncol Pract 3: 12–14.
Shoham Z (1994) Epidemiology, etiology, and fertility drugs in ovarian epithelial carcinoma: where are we today? Fertil Steril 62: 433–448.
Mosgaard BJ, Lidegaard O, Andersen AN (1997) The impact of parity, infertility and treatment with fertility drugs on the risk of ovarian cancer. A survey. Acta Obstet Gynecol Scand 76: 89–95.
Nugent D, Salha O (1998) Ovarian neoplasia and subfertility treatments. Br J Obstet Gynaecol 105: 584–591.
Duckitt K, Templeton AA (1998) Cancer in women with infertility. Curr Opin Obstet Gynecol 10: 199–203.
Glud E, Kjaer SK, Troisi R, Brinton LA (1999) Fertility drugs and ovarian cancer. Epidemiol Rev 20: 237–257.
Heineman MJ (1996) Groeiend inzicht. Utrecht (NL): Wet-enschappelijke Uitgeverij Bunge.
Glasier AF (1990) Clomiphene citrate. BaillieÁres Clin Obstet Gynaecol 4: 491–501.
Clark JH, Markaverich BM (1981) The agonistic-antagonistic properties of clomiphene: a review. Pharmacol Ther 15: 467–519.
Mikkelson TJ, Kroboth PD, Cameron WJ, Dittert LW, Chungi V, Manberg PJ (1986) Single-dose pharmacokinetics of clomiphene citrate in normal volunteers. Fertil Steril 46: 392–396.
Derman SG, Adashi EY (1994) Adverse effects of fertility drugs. Drug Saf 11: 408–421.
Brown JB (1978) Pituitary control of ovarian function-concepts derived from gonadotrophin therapy. Aust NZ J Obstetynaecol 18: 46–54.
Baird DT (1987) A model for follicular selection and ovulation: lessons from superovulation. J Steroid Biochem 27: 15–23.
Fishel S, Jackson P (1989) Follicular stimulation for high tech pregnancies: are we playing it safe? BMJ 299: 309–311.
March CM (1993) Ovulation induction. J Reprod Med 38: 335–346.
Landis SH, Murray T, Bolden S, Wingo PA (1998) Cancer statistics, 1998. CA Cancer J Clin 48: 6–29.
Ries LAG, Kosary CL, Hankey BF, Miller BA, Edwards BK (1998) SEER Cancer Statistics Review, 1973–1995. Bethesda, MD: National Cancer Institute.
Adami HO, Bergstrom R, Persson I, Sparen P (1990) The incidence of ovarian cancer in Sweden, 1960–1984. Am J Epidemiol 132: 446–452.
Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J (1997) Cancer Incidence in Five Continents, Vol. VII. Lyon: IARC Scientific Publication No. 143.
Doyle P, dos Santos Silva I (1996) Pathogenesis and epidemiol-ogy of ovarian cancer. In: Shingleton HM, Fowler WCJ, Jordan JA, Lawrence WD, eds. Gynecologic Oncology. Current Diagnosis and Treatment. London: WB Saunders, pp. 165–173.
The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development (1987) The reduction in risk of ovarian cancer associated with oral-contraceptive use. N Engl J Med 316: 650–655.
Negri E, Franceschi S, Tzonou A, et al. (1991) Pooled analysis of 3 European case-control studies: I. Reproductive factors and risk of epithelial ovarian cancer. Int J Cancer 49: 50–56.
Fathalla MF (1971) Incessant ovulation a factor in ovarian neoplasia? Lancet 2: 163.
Adami HO, Hsieh CC, Lambe M, et al. (1994) Parity, age at first childbirth, and risk of ovarian cancer. Lancet 344: 1250–1254.
Albrektsen G, Heuch I, Kvale G (1996) Reproductive factors and incidence of epithelial ovarian cancer: a Norwegian prospective study. Cancer Causes Control 7: 421–427.
Stadel BV (1975) Letter: The etiology and prevention of ovarian cancer. Am J Obstet Gynecol 123: 772–774.
Cramer DW, Welch WR (1983) Determinants of ovarian cancer risk. II. Inferences regarding pathogenesis. J Natl Cancer Inst 71: 717–721.
Risch HA (1998) Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and proges terone. J Natl Cancer Inst 90: 1774–1786.
Lux-Lantos VA, Thyssen SM, Chamson A, Libertun C (1995) E.ect of a gonadotropin releasing hormone analog on an experimental ovarian tumor: direct and indirect actions. Life Sci 57: 291–300.
Blaakaer J, Baeksted M, Micic S, Albrectsen P, Rygaard J, Bock J (1995) Gonadotropin-releasing hormone agonist suppres-sion of ovarian tumorigenesis in mice of the Wx/Wv genotype. Biol Reprod 53: 775–779.
McGowan L, Davis RH (1970) Intrasplenic ovarian grafts in Syrian hamsters and peritoneal fluid cellular distribution. Proc Soc Exp Biol Med 134: 507–509.
Rao AR (1981) Effects of carcinogen and/or mutagen on normal and gonadtotropin-primed ovaries of mice. Int J Cancer 28: 105–110.
Bengtsson M, Rydstrom J (1983) Regulation of carcinogen metabolism in the rat ovary by the estrous cycle and gonadotropin. Science 219: 1437–1438.
Simon WE, Holzel F (1979) Hormone sensitivity of gynecological tumor cells in tissue culture. J Cancer Res Clin Oncol 94: 307–323.
Simon WE, Albrecht M, Hansel M, Dietel M, Holzel F (1983) Cell lines derived from human ovarian carcinomas: growth stimulation by gonadotropic and steroid hormones. J Natl Cancer Inst 70: 839–845.
Henderson BE, Ross R, Bernstein L (1988) Estrogens as a cause of human cancer: the Richard and Hinda Rosenthal Foundation award lecture. Cancer Res 48: 246–253.
Cook LS, Kamb ML, Weiss NS (1997) Perineal powder exposure and the risk of ovarian cancer. Am J Epidemiol 145: 459–465.
Blejer HP, Arlon R (1973) Talc: a possible occupational and environmental carcinogen. J Occup Med 15: 92–97.
Graham J, Graham R (1967) Ovarian cancer and asbestos. Environ Res 1: 115–128.
Henderson WJ, Joslin CA, Turnbull AC, Griffiths K (1971) Talc and carcinoma of the ovary and cervix. J Obstet Gynaecol Br Commonw 78: 266–272.
Longo DL, Young RC (1979) Cosmetic talc and ovarian cancer. Lancet 2: 349–351.
Newhouse ML (1979) Cosmetic talc and ovarian cancer. Lancet 2: 528.
Parmley TH, Woodru. JD (1974) The ovarian mesothelioma. Am J Obstet Gynecol 120: 234–241.
Roe FJ (1979) Controversy: cosmetic talc and ovarian cancer. Lancet 2: 744.
Whittemore AS, Wu ML, Paffenbarger RS Jr, et al. (1988) Personal and environmental characteristics related to epithelial ovarian cancer. II. Exposures to talcum powder, tobacco, alcohol, and coffee. Am J Epidemiol 128: 1228–1240.
Rosenblatt KA, Szklo M, Rosenshein NB (1992) Mineral fiber exposure and the development of ovarian cancer. Gynecol Oncol 45: 20–25.
Cramer DW, Welch WR, Scully RE, Wojciechowski CA (1982) Ovarian cancer and talc: a case-control study. Cancer 50: 372–376.
Hartge P, Hoover R, Lesher LP, McGowan L (1983) Talc and ovarian cancer. JAMA 250: 1844.
Booth M, Beral V, Smith P (1989) Risk factors for ovarian cancer: a case-control study. Br J Cancer 60: 592–598.
Harlow BL, Cramer DW, Bell DA, Welch WR (1992) Perineal exposure to talc and ovarian cancer risk. Obstet Gynecol 80: 19–26.
Chen Y, Wu PC, Lang JH, Ge WJ, Hartge P, Brinton LA (1992) Risk factors for epithelial ovarian cancer in Beijing, China. Int J Epidemiol 21: 23–29.
Paulson RJ (1997) Fertility drugs and ovarian epithelial cancer: the endometriosis hypothesis. J Assist Reprod Genet 14: 228–230.
Hankinson SE, Hunter DJ, Colditz GA, et al. (1993) Tubal ligation, hysterectomy, and risk of ovarian cancer. A prospective study. JAMA 270: 2813–2818.
Green A, Purdie D, Bain C, et al. (1997) Tubal sterilisation, hysterectomy and decreased risk of ovarian cancer. Survey of Women's Health Study Group. Int J Cancer 71: 948–951.
Parazzini F, Negri E, La Vecchia C, Luchini L, Mezzopane R (1993) Hysterectomy, oophorectomy, and subsequent ovarian cancer risk. Obstet Gynecol 81: 363–366.
Irwin KL, Weiss NS, Lee NC, Peterson HB (1991) Tubal sterilization, hysterectomy, and the subsequent occurrence of epithelial ovarian cancer. Am J Epidemiol 134: 362–369.
Sightler SE, Boike GM, Estape RE, Averette HE (1991) Ovarian cancer in women with prior hysterectomy: a 14–year experience at the University of Miami. Obstet Gynecol 78: 681–684.
Helzhouer KJ, Alberg AJ, Gordon GB, et al. (1995) Serum gonadotropins and steroid hormones and the development of ovarian cancer. JAMA 274: 1926–1930.
McGowan L, Parent L, Lednar W, Norris HJ (1979) The women at risk for developing ovarian cancer. Gynecol Oncol 7: 325–344.
Joly DJ, Lilienfeld AM, Diamond EL, Bross ID (1974) An epidemiologic study of the relationship of reproductive experience to cancer of the ovary. Am J Epidemiol 99: 190–209.
Cramer DW, Hutchison GB, Welch WR, Scully RE, Ryan KJ (1983) Determinants of ovarian cancer risk. I. Reproductive experiences and family history. J Natl Cancer Inst 71: 711–716.
Hartge P, Schiffman MH, Hoover R, McGowan L, Lesher L, Norris HJ (1989) A case-control study of epithelial ovarian cancer. Am J Obstet Gynecol 161: 10–16.
Whittemore AS, Wu ML, Pa.enbarger RS Jr, et al. (1989) Epithelial ovarian cancer and the ability to conceive. Cancer Res 49: 4047–4052.
Risch HA, Weiss NS, Lyon JL, Daling JR, Li. JM (1983) Events of reproductive life and the incidence of epithelial ovarian cancer. Am J Epidemiol 117: 128–139.
Risch HA, Marrett LD, Howe GR (1994) Parity, contraception, infertility, and the risk of epithelial ovarian cancer. Am J Epidemiol 140: 585–597.
John EM, Whittemore AS, Harris R, Itnyre J (1993) Characteristics relating to ovarian cancer risk: collaborative analysis of seven US case-control studies. Epithelial ovarian cancer in black women. Collaborative Ovarian Cancer Group. J Natl Cancer Inst 85: 142–147.
Horn-Ross PL, Whittemore AS, Harris R, Itnyre J (1992) Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. VI. Nonepithelial cancers among adults. Collaborative Ovarian Cancer Group. Epidemiology 3: 490–495.
Whittemore AS, Harris R, Itnyre J, Halpern J (1992) Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. I. Methods. Collaborative Ovarian Cancer Group. Am J Epidemiol 136: 1175–1183.
Whittemore AS, Harris R, Itnyre J (1992) Characteristics relating to ovarian cancer risk: collaborative analysis of 12UScase-control studies. IV. The pathogenesis of epithelial ovarian cancer. Collaborative Ovarian Cancer Group. Am J Epidemiol 136: 1212–1220.
Komatsu T, Konishi I, Mandai M, et al. (1995) Peritoneal papillary serous carcinoma arising in an infertile woman during ovulation-induction therapy: immunohistochemical expression of LH/hCG receptors. Gynecol Oncol 56: 470–474.
Bristow RE, Karlan BY (1997) Stage IV ovarian carcinoma following ovulation induction: a report of three cases. Int J Gynecol Cancer 7: 112–116.
Atlas M, Menczer J (1982) Massive hyperstimulation and borderline carcinoma of the ovary. A possible association. Acta Obstet Gynecol Scand 61: 261–263.
Bamford PN, Steele SJ (1982) Uterine and ovarian carcinoma in a patient receiving gonadotrophin therapy. Case report. Br J Obstet Gynaecol 89: 962–964.
Ben-Hur H, Dgani R, Lancet M, Katz Z, Nissim F, Rosenman D (1986) Ovarian carcinoma masquerading as ovarian hyperstimulation syndrome. Acta Obstet Gynecol Scand 65: 813–814.
Carter ME, Joyce DN (1987) Ovarian carcinoma in a patient hyperstimulated by gonadotropin therapy for in vitro fertilization: a case report. J In Vitro Fert Embryo Transf 4: 126–128.
Kulkarni R, McGarry JM (1989) Follicular stimulation and ovarian cancer. BMJ 299: 740.
Dietl J (1991) Ovulation and ovarian cancer. Lancet 338: 445.
Goldberg GL, Runowicz CD (1992) Ovarian carcinoma of low malignant potential, infertility, and induction of ovulation is there a link? Am J Obstet Gynecol 166: 853–854.
Lopes P, Mensier A (1993) Ovarian cancer and assisted reproductive technology. Eur J Obstet Gynecol Reprod Biol 51: 171–173.
Balasch J, Barri PN (1993) Follicular stimulation and ovarian cancer? Hum Reprod 8: 990–996.
Karlan BY, Marrs R, Lagasse LD (1994) Advanced-stage ovarian carcinoma presenting during infertility evaluation. Am J Obstet Gynecol 171: 1377–1378.
Ismail SM, Walker SM (1990) Bilateral virilizing sclerosing stromal tumours of the ovary in a pregnant woman with Gorlin's syndrome: implications for pathogenesis of ovarian stromal neoplasms. Histopathology 17: 159–163.
Grimbizis G, Tarlatzis BC, Bontis J, et al. (1995) Two cases of ovarian tumours in women who had undergone multiple ovarian stimulation attempts. Hum Reprod 10: 520–523.
Bandera CA, Cramer DW, Friedman AJ, Sheets EE (1995) Fertility therapy in the setting of a history of invasive epithelial ovarian cancer. Gynecol Oncol 58: 116–119.
Nijman HW, Burger CW, Baak JP, Schats R, Vermorken JB, Kenemans P (1992) Borderline malignancy of the ovary and controlled hyperstimulation, a report of 2 cases. Eur J Cancer 28A: 1971–1973.
Willemsen W, Kruitwagen R, Bastiaans B, Hanselaar T, Rolland R (1993) Ovarian stimulation and granulosa-cell tumour. Lancet 341: 986–988.
Unkila-Kallio L, Leminen A, Tiitnen A, Lehtovirta P, Wahlstrom T, Ylikorkala O (1997) Malignant tumors of the ovary or the breast in association with infertility: a report of thirteen cases. Acta Obstet Gynecol Scand 76: 177–181.
Nasca PC, Greenwald P, Chorost S, Richart R, Caputo T (1984) An epidemiologic case-control study of ovarian cancer and reproductive factors. Am J Epidemiol 119: 705–713.
Buitendijk SE, Verkerk PH, Verloove-Vanhorick SP (1993) Fertility enhancing drugs and ovarian carcinoma. [Dutch]. Ned Tijdschr Geneeskd 137: 1643–1644.
Spirtas R, Kaufman SC, Alexander NJ (1993) Fertility drugs and ovarian cancer: red alert or red herring? Fertil Steril 59: 291–293.
Cohen J, Forman R, Harlap S, et al. (1993) IFFS expert group report on the Whittemore study related to the risk of ovarian cancer associated with the use of infertility agents. Hum Reprod 8: 996–999.
Evers JL (1993) Fertility-promoting drugs and ovarian carcinoma. [Dutch]. Ned Tijdschr Geneeskd 137: 1993–1994.
Caro JJ, Johannes CB, Hartz SC, Marrs R, Miettinen OS (1993) Re: ``Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women''. Am J Epidemiol 137: 928–929.
Land JA (1993) Ovulation, ovulation induction and ovarian carcinoma. Baillieres Clin Obstet Gynaecol 7: 455–472.
Rossing MA, Daling JR, Weiss NS (1995) Risk of ovarian cancer after treatment for infertility. N Engl J Med 332: 1302.
Harlow BL, Weiss NS, Roth GJ, Chu J, Daling JR (1988) Case-control study of borderline ovarian tumors: reproductive history and exposure to exogenous female hormones. Cancer Res 48: 5849–5852.
Jansen R (1993) Ovarian stimulation and granulosa-cell tumour. Lancet 341: 1345.
Kelsey JL, Horn-Ross PL (1993) Breast cancer: magnitude of the problem and descriptive epidemiology. Epidemiol Rev 15: 7–16.
Kelsey JL, Bernstein L (1996) Epidemiology and prevention of breast cancer. Annu Rev Public Health 17: 47–67.
Collaborative Group on Hormonal Factors in Breast Cancer (1996) Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. Lancet 347: 1713–1727.
Rookus MA, van Leeuwen FE (1994) Oral contraceptives and risk of breast cancer in women aged 20–54 years. Netherlands Oral Contraceptives and Breast Cancer Study Group. Lancet 344: 844–851.
Colditz GA, Hankinson SE, Hunter DJ, et al. (1995) The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 332: 1589–1593.
Beral V, Banks E, Reeves G, Wallis M (1997) Hormone replacement therapy and high incidence of breast cancer between mammographic screens. Lancet 349: 1103–1104.
Collaborative Group on Hormonal Factors in Breast Cancer (1997) Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 350: 1047–1059.
Key TJ, Pike MC (1988) The role of oestrogens and progestagens in the epidemiology and prevention of breast cancer. Eur J Cancer Clin Oncol 24: 29–43.
Henderson BE, Ross RK, Judd HL, Krailo MD, Pike MC (1985) Do regular ovulatory cycles increase breast cancer risk? Cancer 56: 1206–1208.
Brzezinski A, Peretz T, Mor-Yosef S, Schenker JG (1994) Ovarian stimulation and breast cancer: is there a link? Gynecol Oncol 52: 292–295.
Bolton PM (1977) Bilateral breast cancer associated with clomiphene. Lancet 2: 1176.
Arbour L, Narod S, Glendon G, et al. (1994) In-vitro fertilisation and family history of breast cancer. Lancet 344: 610–611.
Laing RW, Glaser MG, Barrett GS (1989) A case of breast carcinoma in association with in vitro fertilization. J R Soc Med 82: 503.
Sutherland RL, Watts CK, Hall RE, Ruenitz PC (1987) Mechanisms of growth inhibition by nonsteroidal antioestro-gens in human breast cancer cells. J Steroid Biochem 27: 891–897.
Colditz GA, Rosner B (1998) Use of estrogen plus progestin is associated with greater increase in breast cancer than estrogen alone. Am J Epidemiol 147: (Abstract).
Sta.a JA, Newscha.er CJ, Jones JK, Miller V (1992) Progestins and breast cancer: an epidemiologic review. Fertil Steril 57: 473–491.
Lambe M, Hsieh C, Trichopoulos D, Ekbom A, Pavia M, Adami HO (1994) Transient increase in the risk of breast cancer after giving birth. N Engl J Med 331: 5–9.
Kroman N, Wohlfahrt J, Andersen KW, Mouridsen HT, Westergaard T, Melbye M (1997) Time since childbirth and prognosis in primary breast cancer: population based study. BMJ 315: 851–855.
Kvale G, Heuch I, Nilssen S (1991) Reproductive factors and cancers of the breast and genital organs are the different cancer sites similarly affected? Cancer Detect Prev 15: 369–377.
Henderson BE, Casagrande JT, Pike MC, Mack T, Rosario I, Duke A (1983) The epidemiology of endometrial cancer in young women. Br J Cancer 47: 749–756.
Jensen H (1985) Endometrial carcinoma. A retrospective, epidemiological study. Dan Med Bull 32: 219–228.
Pettersson B, Adami HO, Bergstrom R, Johansson ED (1986) Menstruation span a time-limited risk factor for endometrial carcinoma. Acta Obstet Gynecol Scand 65: 247–255.
Parazzini F, La Vecchia C, Negri E, Fedele L, Balotta F (1991) Reproductive factors and risk of endometrial cancer. Am J Obstet Gynecol 164: 522–527.
Brinton LA, Berman ML, Mortel R, et al. (1992) Reproductive, menstrual, and medical risk factors for endometrial cancer: results from a case-control study. Am J Obstet Gynecol 167: 1317–1325.
van Leeuwen FE, Rookus MA (1989) The role of exogenous hormones in the epidemiology of breast, ovarian and endometrial cancer. Eur J Cancer Clin Oncol 25: 1961–1972.
Brinton LA, Hoover RN (1993) Estrogen replacement therapy and endometrial cancer risk: unresolved issues. The Endometrial Cancer Collaborative Group. Obstet Gynecol 81: 265–271.
Jick SS, Walker AM, Jick H (1993) Estrogens, progesterone, and endometrial cancer. Epidemiology 4: 20–24.
Voigt LF, Weiss NS, Chu J, Daling JR, McKnight B, van Belle G (1991) Progestagen supplementation of exogenous oestrogens and risk of endometrial cancer. Lancet 338: 274–277.
Beresford SA, Weiss NS, Voigt LF, McKnight B (1997) Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women. Lancet 349: 458–461.
Weiss NS, Sayvetz TA (1980) Incidence of endometrial cancer in relation to the use of oral contraceptives. N Engl J Med 302: 551–554.
Kaufman DW, Shapiro S, Slone D, et al. (1980) Decreased risk of endometrial cancer among oral-contraceptive users. N Engl J Med 303: 1045–1047.
Hulka BS, Chambless LE, Kaufman DG, Fowler WC Jr, Greenberg BG (1982) Protection against endometrial carcinoma by combination-product oral contraceptives. JAMA 247: 475–477.
The Centers for Disease Control Cancer and Steroid Hormone Study (1983) Oral contraceptive use and the risk of endometrial cancer. JAMA 249: 1600–1604.
Rosenblatt KA, Thomas DB (1991) Hormonal content of com-bined oral contraceptives in relation to the reduced risk of en-dometrial carcinoma. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Int J Cancer 49: 870–874.
Key TJ (1995) Hormones and cancer in humans. Mutat Res 333: 59–67.
Key TJ, Pike MC (1988) The dose-effect relationship between ``unopposed'' oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk. Br J Cancer 57: 205–212.
Dahlgren E, Friberg LG, Johansson S, et al. (1991) Endometrial carcinoma; ovarian dysfunction-a risk factor in young women. Eur J Obstet Gynecol Reprod Biol 41: 143–150.
Elwood JM, Cole P, Rothman KJ, Kaplan SD (1977) Epidemiology of endometrial cancer. J Natl Cancer Inst 59: 1055–1060.
Kelsey JL, LiVolsi VA, Holford TR, et al. (1982) A case-control study of cancer of the endometrium. Am J Epidemiol 116: 333–342.
Wynder EL, Escher GC, Mantel N (1966) An epidemiological investigation of cancer of the endometrium. Cancer 19: 489–520.
Stadel BV (1976) Dietary iodine and risk of breast, endometrial, and ovarian cancer. Lancet 1: 890–891.
La Vecchia C, Franceschi S, Gallus G, et al. (1982) Oestrogens and obesity as risk factors for endometrial cancer in Italy. Int J Epidemiol 11: 120–126.
Holly EA, Cress RD, Ahn DK (1994) Cutaneous melanoma in women: ovulatory life, menopause, and use of exogenous estrogens. Cancer Epidemiol Biomarkers Prev 3: 661–668.
Gallagher RP, Elwood JM, Hill GB, Coldman AJ, Threlfall WJ, Spinelli JJ (1985) Reproductive factors, oral contraceptives and risk of malignant melanoma: Western Canada Melanoma Study. Br J Cancer 52: 901–907.
Green A, Bain C (1985) Hormonal factors and melanoma in women. Med J Aust 142: 446–448.
Holman CD, Armstrong BK, Heenan PJ (1984) Cutaneous malignant melanoma in women: exogenous sex hormones and reproductive factors. Br J Cancer 50: 673–680.
Beral V, Ramcharan S, Faris R (1977) Malignant melanoma and oral contraceptive use among women in California. Br J Cancer 36: 804–809.
Kuppens E, Bergman W, Welvaart K, Bruijn JA, Sche.er E (1992) Multiple primary melanomas in a patient with familial-type DNS during clomiphene-induced pregnancy. Melanoma Res 2: 71–74.
Ron E, Kleinerman RA, Boice JD Jr, LiVolsi VA, Flannery JT, Fraumeni JF Jr (1987) A population-based case-control study of thyroid cancer. J Natl Cancer Inst 79: 1–12.
Preston-Martin S, Bernstein L, Pike MC, Maldonado AA, Henderson BE (1987) Thyroid cancer among young women related to prior thyroid disease and pregnancy history. Br J Cancer 55: 191–195.
McTiernan AM, Weiss NS, Daling JR (1984) Incidence of thyroid cancer in women in relation to reproductive and hormonal factors. Am J Epidemiol 120: 423–435.
Galanti MR, Lambe M, Ekbom A, Sparen P, Pettersson B (1995) Parity and risk of thyroid cancer: a nested case-control study of a nationwide Swedish cohort. Cancer Causes Control 6: 37–44.
Christov K (1975) Thyroid cell proliferation in rats and induction of tumors by X-rays. Cancer Res 35: 1256–1262.
Chan V, Paraskevaides CA, Hale JF (1975) Assessment of thyroid function during pregnancy. Br J Obstet Gynaecol 82: 137–141.
Osathanondh R, Tulchinsky D, Chopra IJ (1976) Total and free thyroxine and triiodothyronine in normal and complicated pregnancy. J Clin Endocrinol Metab 42: 98–104.
Weeke J, Hansen AP (1975) Serumfitsh and serum t3 levels during normal menstrual cycles and during cycles on oral contraceptives. Acta Endocrinol 79: 431–438.
La Vecchia C, Ron E, Franceschi S, et al. (1999) A pooled analysis of case-control studies of thyroid cancer. III. Oral contraceptives, menopausal replacement therapy and other female hormones. Cancer Causes Control 10: 157–166.
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Klip, H., Burger, C.W., Kenemans, P. et al. Cancer Risk Associated with Subfertility and Ovulation Induction: A Review. Cancer Causes Control 11, 319–344 (2000). https://doi.org/10.1023/A:1008921211309
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DOI: https://doi.org/10.1023/A:1008921211309