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Globally, ovarian cancer is the sixth most common cancer among women. The annual incidence rates of ovarian cancer, age-adjusted to the world population, differ among geographic areas. Especially high rates are reported in Scandinavia (15/100 000). In Northern America and western Europe the rates are intermediate (10/100 000), while developing countries and Japan have low rates (3/100 000) (Parkin et al., 1993). The life-time risk for a woman to develop ovarian cancer is 1–2% in high incidence areas. As most cases are diagnosed at an advanced stage the prognosis is poor, with 5-year survival rates less than 40%. Annually more than 100 000 women are estimated to die from the disease (Pisani et al., 1993).

The vast majority of epithelial ovarian cancers are sporadic, while 5–10% are estimated to be inherited (Narod et al., 1994). The breast–ovarian cancer syndrome is the most common inherited type and has been linked to germline mutations in the BRCA1 tumour-suppressor gene (Narod et al., 1991), which was cloned in 1994 (Miki et al., 1994). The estimated risk among BRCA1 carriers to develop an ovarian malignancy by age 70 is 63%, and the prevalence of carriers in the general population is 1/800 (Ford & Easton, 1995).

Epithelial ovarian tumours, germ cell tumours and sex cord/stromal tumours are the major types of ovarian tumours. Epithelial ovarian tumours are derived from the surface epithelium and typically constitute 80–90% of ovarian malignancies. Of the epithelial tumours, approximately 15% are of borderline malignant potential while the rest are invasive cancers. There are several histopathological subgroups of epithelial ovarian cancers (Slotman & Rao, 1988). In an English case–control study the epithelial ovarian cancers were distributed as follows: serous adenocarcinoma (43%), mucinous adenocarcinoma (15%), endometroid adenocarcinoma (22%), clear cell adenocarcinoma (5%) and mixed or undifferentiated tumours (14%) (Booth et al., 1989). Similar results have been reported in a recent Norwegian project (Björge et al., 1997).

This review will focus on how reproductive factors, hormonal contraceptives, hormone replacement therapy, hormonal infertility treatment and common gynecological operations are related to epithelial ovarian cancer epidemiology. First, some possible aetiological aspects will be discussed.

Aetiology

  1. Top of page
  2. Aetiology
  3. Age at menarche and menopause
  4. Parity and pregnancy
  5. Lactation
  6. Combined oral contraceptives
  7. Progestin-only contraceptives
  8. Hormone replacement therapy
  9. Infertility and ovulation induction
  10. Tubal ligation and hysterectomy
  11. Summary
  12. References

The causes of ovarian cancer are poorly understood. Reproductive hormones are thought to be involved in the aetiology. For many years the ‘incessant ovulation’ (Fathalla, 1971) and ‘gonadotrophin’ hypotheses (Stadel, 1975) have been connected to ovarian carcinogenesis. These hypotheses find support in epidemiological research, and recent progress in molecular biology augments the insight on possible aetiological mechanisms at the cellular level (Godwin et al., 1993; Boyd & Rubin, 1997). Other hypotheses explore the retrograde transport of contaminants (Cramer et al., 1982) or endogenous carcinogens (Cramer & Xu, 1995) through the Fallopian tubes. A new hypothesis proposes a pregnancy-dependent clearance of transformed malignant cells from the ovaries (Adami et al., 1994).

The ‘incessant ovulation’ hypothesis suggests that the risk of epithelial ovarian cancer increases with the number of ovulations, as the traumatized epithelium of ruptured follicles is recurrently repaired and exposed to oestrogen-rich follicular fluid. Growth factors are believed to influence post-ovulatory repair, and impaired regulation of growth factors may be involved in malignant transformation. Epithelial growth factor (EGF) stimulated growth in several human ovarian cancer cell-lines (Berchuck et al., 1990). Cells from epithelial ovarian cancers frequently express the EGF transmembrane receptor (Bauknecht et al., 1988; Berchuck et al., 1991; Rodriguez et al., 1991; Ilekis et al., 1997) and also secrete growth factors (Berchuck et al., 1990), indicating the possibility of growth regulatory autocrine loops. Oestrogen has been shown to be mitogenic to ovarian epithelium (Nash et al., 1989), an effect possibly mediated through altered growth factor levels. Local steroid production has been found in human epithelial ovarian tumours (Ridderheim et al., 1993; Abrahamsson et al., 1997), and steroid receptors are present in many ovarian tumours. In a review 62% of malignant ovarian tumours contained receptors for oestrogen, 49% for progesterone, 69% for androgen, while 49% of the tumours had both oestrogen and progesterone receptors (Rao & Slotman, 1991). Recent studies also report a high prevalence of androgen receptors (Ilekis et al., 1997). The exact biological relevance of local hormone production and expression of steroid receptors in ovarian cancers is still unresolved. Cytokines also seem to regulate both normal and malignant ovarian epithelium (Malik & Balkwill, 1991).

In support of the ‘incessant ovulation’ hypothesis, experiments on rat surface epithelial ovarian cells propagated in cell-culture showed loss of contact inhibition, and when late passage cells were transplanted into mice, tumours developed and chromosomal aberrations occurred (Godwin et al., 1992). Subsequently, in models with continuously proliferating rat ovarian surface epithelial cells a probable tumour-suppressor gene, LOT-1 (lost on transformation 1), has been identified and recently its human homologue has been cloned and characterized (Abdollahi et al., 1997). Further evidence is presented in a recent molecular case–control study where women with a greater mean number of ovulatory cycles had a significantly increased risk of developing p53-positive but not p53-negative ovarian cancers (Schildkraut et al., 1997). The p53-positive cancers overexpress mutant p53 protein and reflect DNA damage to the p53 tumour-suppressor gene. Normal p53 protein does not accumulate in the cell and acts in the repair of damaged DNA. The loss of normal p53 protein may increase the risk for propagation of DNA-damaged cells and malignant transformation. Spontaneous mutations in the ERB-B2 and K-RAS proto-oncogenes are thought to play a role in sporadic ovarian carcinogenesis (Boyd & Rubin, 1997).

The ‘gonadotrophin’ hypothesis predicts that high levels of pituitary gonadotrophins increase cancer risk by stimulating the ovarian surface epithelium. This situation pertains especially to the early post-menopausal years when both gonadotrophin levels and the age-specific incidence of epithelial ovarian cancer are high. In animal models elevated gonadotrophin levels have been associated with tumour development (Biskind & Biskind, 1944) and gonadotrophin suppression by a GnRH-agonist in mice that are genetically manipulated to develop ovarian tumours inhibited tumourgenesis (Blaakaer et al., 1995). Human ovarian cancer cell lines were stimulated by gonadotrophins in vitro (Simon et al., 1983). Gonadotrophin receptors have been found in both benign and malignant ovarian tumours by several investigators (Kammerman et al., 1981; Rajaniemi et al., 1981), but not by others (Stouffer et al., 1984). In a case–control study women with PCO (polycystic ovary syndrome), had an increased risk of developing epithelial ovarian carcinoma (Schildkraut et al., 1996). Women with PCO have an elevated LH/FSH (luteinizing hormone/follicle stimulating hormone) ratio. In a cohort study lower prediagnostic FSH levels were found among women who eventually developed ovarian cancer, a finding that contradicts the ‘gonadotrophin’ hypothesis (Helzlsouer et al., 1995).

Age at menarche and menopause

  1. Top of page
  2. Aetiology
  3. Age at menarche and menopause
  4. Parity and pregnancy
  5. Lactation
  6. Combined oral contraceptives
  7. Progestin-only contraceptives
  8. Hormone replacement therapy
  9. Infertility and ovulation induction
  10. Tubal ligation and hysterectomy
  11. Summary
  12. References

Early age at menarche and late age at natural menopause supposedly increase the number of ovulatory cycles, although cycles soon after menarche and in the years preceding menopause often may be anovulatory. In support of the ‘incessant ovulation’ hypothesis, an early age at menarche and a late age at menopause should increase the risk of epithelial ovarian cancer. On the contrary, a late age at menopause delays the risk in post-menopausal gonadotrophins and possibly decreases risk according to the ‘gonadotrophin hypothesis’.

Many epidemiologists have investigated the relation between menstrual history and the risk of epithelial ovarian cancer. A number of studies have found a weak risk increase with menarche at a young age. Odds ratios in these studies range from 1.1 to 1.5 when comparing menarche before 12 years with more than 14 years of age, and often are not statistically significant (Wynder et al., 1969; Wu et al., 1988; Booth et al., 1989; Parazzini et al., 1989; Tavani et al., 1993; Hankinson et al., 1995; Purdie et al., 1995). In a Chinese study, a significant protection from epithelial ovarian cancer was found with late age at menarche, and in this study population it was common with menarche after 18 years of age (Shu et al., 1989). In other studies no association between the age at menarche and epithelial ovarian cancer risk emerged (Newhouse et al., 1977; Casagrande et al., 1979; McGowan et al., 1979; Hildreth et al., 1981; Kvåle et al., 1988; Franceschi et al., 1991; Polychronopoulou et al., 1993). One study showed a slight increased risk with late age at menarche (Tzonou et al., 1984).

A direct relationship between age at natural menopause and ovarian cancer risk was found in several case–control studies, with relative risk estimates across studies from 1.4 to 4.6 for the oldest menopause category (Hildreth et al., 1981; Tzonou et al., 1984; Wu et al., 1988; Booth et al., 1989; Parazzini et al., 1989; Shu et al., 1989; Franceschi et al., 1991; Polychronopoulou et al., 1993). The increased risk from late menopause persisted also among older women (Parazzini et al., 1989). No association between age at menopause and ovarian cancer risk was found in two cohort (Kvåle et al., 1988; Hankinson et al., 1995) and other case–control studies (Wynder et al., 1969; Annegers et al., 1979; McGowan et al., 1979; Newhouse et al., 1977; Cramer et al., 1983; Hartge et al., 1988; Whittemore et al., 1992).

The divergent results among studies indicate that age at menarche and menopause are most probably weak predictors of ovarian cancer risk. The definition of menarche and menopause in epidemiological studies can be subject to recall and misclassification problems, which may explain some of the conflicting results. Possibly a late age at menopause may slightly increase the risk of ovarian cancer.

Parity and pregnancy

  1. Top of page
  2. Aetiology
  3. Age at menarche and menopause
  4. Parity and pregnancy
  5. Lactation
  6. Combined oral contraceptives
  7. Progestin-only contraceptives
  8. Hormone replacement therapy
  9. Infertility and ovulation induction
  10. Tubal ligation and hysterectomy
  11. Summary
  12. References

Pregnancy leads to anovulation and suppresses secretion of pituitary gonadotrophins. In line with both the ‘incessant ovulation’ and the ‘gonadotrophin’ hypotheses, pregnancy is expected to reduce the risk of epithelial ovarian cancer. One of the most consistent findings in ovarian cancer epidemiology is the protective effect of full-term pregnancies on epithelial ovarian cancer risk (Joly et al., 1974; Newhouse et al., 1977; Annegers et al., 1979; Casagrande et al., 1979; Miller et al., 1980; Hildreth et al., 1981; Byers et al., 1983; Cramer et al., 1983; Nasca et al., 1984; Tzonou et al., 1984; Voigt et al., 1986; Wu et al., 1988; Kvåle et al., 1988; McGowan et al., 1988; Mori et al., 1988; Booth et al., 1989; Franceschi 1989; Hartge et al., 1989; Shu et al., 1989; Gwinn et al., 1990; Negri et al., 1991; Lund, 1992; Whittemore et al., 1992; Chen et al., 1992; John et al., 1993; Polychronopoulou et al., 1993; Adami et al., 1994; Baker & Piver, 1994; Risch et al., 1994; Albrektsen et al., 1996). Parous women compared to nulliparous have relative risk estimates in the range of 0.3–0.7 (Annegers et al., 1979; Casagrande et al., 1979; Mori et al., 1988; Shu et al., 1989; Negri et al., 1991; Whittemore et al., 1992; Polychronopoulou et al., 1993). In a large combined analysis of twelve US case–control studies a 40% lowered risk was found for the first full-term pregnancy, and each birth after the first incurred another 14% risk reduction (Whittemore et al., 1992). A significant risk decline with increasing parity, with a relative risk estimate of 0.36 for five or more births, was noticed in a prospective study (Kvåle et al., 1988). Protection of increasing parity was also found in a large case–control study nested in a nationwide cohort of Swedish women, with a trend of 0.81 per pregnancy (Adami et al., 1994). In another investigation a reduced risk from parity emerged only to the third full-term pregnancy, while subsequent pregnancies did not decrease risk further (Albrektsen et al., 1996). In a correlational analysis (Beral et al., 1978) a strong inverse association appeared between completely family size and age standardized mortality ratio from ovarian cancer in different countries and for successive birth cohorts in the United States, England and Wales. A minority of investigators have found only a weak or no association between full-term pregnancies and ovarian cancer risk (Wynder et al., 1969; Tavani et al., 1993). In a recent study a higher risk was associated with increasing parity among BRCA1 carriers (Narod et al., 1995).

The influence of age at firth birth on epithelial ovarian cancer risk is unclear. Many case–control studies with hospital controls have shown a direct positive association with age at first birth (Joly et al., 1974; McGowan et al., 1979; Hildreth et al., 1981; Franceschi et al., 1982; LaVecchia et al., 1984; Booth et al., 1989; Negri et al., 1991; Whittemore et al., 1992; Polychronopoulou et al., 1993; Tavani et al., 1993). In the case–control study nested in a nationwide cohort of Swedish women, a 10% risk reduction for each 5-year increment in age at first birth appeared, and it was also found that the protective effect of full-term pregnancy wanes with time (Adami et al., 1994). A reduced risk with late age at first birth also has been indicated in some case–control studies with population controls (Whittemore et al., 1992; John et al., 1993; Purdie et al., 1995); in one (Gwinn et al., 1990) this effect was restricted to uniparous women only. A prospective investigation found a protective effect from late age at first birth for uniparous women only (Albrektsen et al., 1996). Many research papers reflect no association between age at first birth and epithelial ovarian cancer risk (Wynder et al., 1969; Newhouse et al., 1977; Casagrande et al., 1979; Miller et al., 1980; Szamborski et al., 1981; Cramer et al., 1983; Nasca et al., 1984; Voigt et al., 1986; Kvåle et al., 1988; Mori et al., 1988; Wu et al., 1988; Hartge et al., 1989; Shu et al., 1989; Chen et al., 1992; Lund, 1992; Risch et al., 1994; Hankinson et al., 1995).

The role of incomplete pregnancies on epithelial ovarian cancer risk also remains unsettled. The classification of incomplete pregnancies differ among studies. Sometimes spontaneous and induced abortions are grouped together, at other times they are analysed separately. With an increased number of incomplete pregnancies many investigators have found a protective effect on ovarian cancer risk (Casagrande et al., 1979; Hildreth et al., 1981; Tzonou et al., 1984; Kvåle et al., 1988; Mori et al., 1988; Booth et al., 1989; Chen et al., 1992; Negri et al., 1992; Whittemore et al., 1992; Tavani et al., 1993). Mostly the risk reduction is weak and often is not statistically significant. In other studies no impact of incomplete pregnancies was found (West, 1966; Wynder et al., 1969; Joly et al., 1974; McGowan et al., 1979; Cramer et al., 1983; Wu et al., 1988; Hartge et al., 1989; Shu et al., 1989; Polychronopoulou et al., 1993; Risch et al., 1994; Purdie et al., 1995). Two investigations showed a slightly increased epithelial ovarian cancer risk with one or more incomplete pregnancies (Newhouse et al., 1977; Nasca et al., 1984). Induced abortions were found protective in several studies (Kvåle et al., 1988; Mori et al., 1988; Hartge et al., 1989; Shu et al., 1989; Negri et al., 1992). Other investigators did not find an altered risk with induced abortions (Polychronopoulou et al., 1993; Purdie et al., 1995; Chen et al., 1996). Spontaneous abortions decreased risk in one study (Risch et al., 1994) and did not change risk in others (Mori et al., 1988; Hartge et al., 1989; Shu et al., 1989). Elevated risk with spontaneous abortions appeared in some reports (Wynder et al., 1969; Joly et al., 1974; Chen et al., 1996).

To summarize the epidemiological findings the protective effect of increasing parity on the risk of epithelial ovarian cancer is established. The effect of age at first birth is not settled, but case–control studies with population controls and prospective investigations indicate that a later age at first birth reduces epithelial ovarian cancer risk. Probably incomplete pregnancies also reduce risk, although not as much as full-term pregnancies. The various reproductive variables are interrelated and different adjustment strategies in analyses may fail to establish the importance of each variable and explain some of the conflicting results among studies. Under-reporting and definition of incomplete pregnancies is another concern.

Lactation

  1. Top of page
  2. Aetiology
  3. Age at menarche and menopause
  4. Parity and pregnancy
  5. Lactation
  6. Combined oral contraceptives
  7. Progestin-only contraceptives
  8. Hormone replacement therapy
  9. Infertility and ovulation induction
  10. Tubal ligation and hysterectomy
  11. Summary
  12. References

Lactation suppresses the secretion of pituitary gonadotropins and leads to anovulation, especially in the initial months after delivery. If the ‘incessant ovulation’ and ‘gonadotrophin’ hypotheses are true, lactation can be assumed to reduce the risk of epithelial ovarian cancer. Most studies have found a decreased risk with lactation (Nasca et al., 1984; Schneider, 1987; Wu et al., 1988; Hartge et al., 1989; Gwinn et al., 1990; Whittemore et al., 1992; Rosenblatt et al., 1993; Risch et al., 1994). The magnitude of the risk reduction is usually weak with odds ratios 0.6–0.9, and trends with increasing duration of lactation often are inconsistent. Lactation during the initial months after delivery seems to be more protective than lactation at later time periods. Other studies have found no association between lactation and epithelial ovarian cancer risk (West, 1966; Wynder et al., 1969; Hildreth et al., 1981; Cramer et al., 1983; Chen et al., 1992; Purdie et al., 1995). In two retrospective studies with hospital controls a slight risk increase was found (Mori et al., 1988; Booth et al., 1989). Despite the conflicting results, the overall impression is that lactation protects against epithelial ovarian cancer, especially lactation close after delivery.

Combined oral contraceptives

  1. Top of page
  2. Aetiology
  3. Age at menarche and menopause
  4. Parity and pregnancy
  5. Lactation
  6. Combined oral contraceptives
  7. Progestin-only contraceptives
  8. Hormone replacement therapy
  9. Infertility and ovulation induction
  10. Tubal ligation and hysterectomy
  11. Summary
  12. References

Combined oral contraceptives (OC) contain both oestrogens and progestins. The contraceptive effect comes from a suppressed mid-cycle gonadotrophin surge and inhibited ovulation. Both according to the ‘incessant’ and ‘gondatrophin’ hypotheses OC use is anticipated to decrease the risk of epithelial ovarian cancer. In ovarian cancer epidemiology there is strong evidence that OC use truly reduces cancer risk. Protection from ever use of OC has appeared in a large majority of studies (Newhouse et al., 1977; Annegers et al., 1979; Casagrande et al., 1979; McGowan et al., 1979; Willett et al., 1981; Weiss et al., 1981; Hildreth et al., 1981; Cramer et al., 1982; Franceschi et al., 1982, 1991; LaVecchia et al., 1984; Tzonou et al., 1984; CASH, 1987; Vessey et al., 1987; Beral et al., 1988; Wu et al., 1988; WHO, 1989; Booth et al., 1989; Gwinn et al., 1990; Parazzini et al., 1991; Rosenblatt et al., 1992; Whittemore et al., 1992; Tavani et al., 1993; Risch et al., 1994; Rosenberg et al., 1994; Hankinson et al., 1995; Purdie et al., 1995; Vessey & Painter, 1995). A meta-analysis including 20 studies from the 1970s and the 1990s calculated a summary relative risk of 0.64 (95% confidence interval 0.57–0.73) for ever use of OC (Hankinson et al., 1992). One study found no association between OC use and epithelial ovarian cancer risk (Hartge et al., 1989). The only outlier is a Chinese case–control study, where an odds ratio of 1.8 (95% confidence interval 0.8–4.1) was found (Shu et al., 1989).

Longer duration of OC use seems to increase the protection against epithelial ovarian cancer. In most studies a risk reduction related to duration appears after several years of OC use (Casagrande et al., 1979; Weiss et al., 1981; Willett et al., 1981; Hildreth et al., 1981; Cramer et al., 1982; LaVecchia et al., 1984; CASH, 1987; Beral et al., 1988; Wu et al., 1988; Booth et al., 1989; WHO, 1989; Parazzini et al., 1991; Whittemore et al., 1992; Tavani et al., 1993; Risch et al., 1994; Rosenberg et al., 1994; Hankinson et al., 1995; Purdie et al., 1995; Vessey & Painter, 1995). Some studies suggest that short term OC use (<1 year) may lead to a decreased risk (Cramer et al., 1982; Rosenberg et al., 1982; CASH, 1987; WHO, 1989; Whittemore et al., 1992). In a review a 50% reduced risk was calculated after 5 years on the pill (Stanford, 1991). A similar result was documented in a meta-analysis (Hankinson et al., 1992), with each year of OC use contributing 10–12% to the risk reduction.

The protective effect of OC seems to last for a long time after the cessation of use. A 40–70% risk reduction persisted when at least 10 years had elapsed since last use (Cramer et al., 1982; CASH, 1987; Booth et al., 1989; WHO, 1989; Rosenblatt et al., 1992; Whittemore et al., 1992; Rosenberg et al., 1994). In some studies a relative risk of about 0.5 remained after 15 years off the pill (CASH, 1987; Booth et al., 1989; WHO, 1989; Franceschi et al., 1991; Rosenberg et al., 1994). An increased risk with longer time since last use of OC is only reported in one study (Hartge et al., 1989).

OC use appears to protect against epithelial ovarian cancer across various strata of parity. In the above cited meta-analysis a summary relative risk of 0.55 was found for both nulliparous and parous women (Hankinson et al., 1992). An effect modification of parity on the relation between OC use and epithelial ovarian cancer may exist. A stronger protection among nulliparous women was found in some studies (Willett et al., 1981; CASH, 1987; Booth et al., 1989; WHO, 1989; Risch et al., 1994), while the opposite emerged in others (McGowan et al., 1979; Weiss et al., 1981; Cramer et al., 1982; Rosenberg et al., 1982; LaVecchia et al., 1984; Vessey & Painter, 1995).

The protection of OC use on epithelial ovarian cancer risk seems to be present at all ages at diagnosis (LaVecchia et al., 1984; CASH, 1987; Beral et al., 1988; Booth et al., 1989; WHO, 1989; Parazzini et al., 1991; Rosenberg et al., 1994). Most studies indicate that lowered risk estimates by OC use do not change with age (CASH, 1987; WHO, 1989; Rosenberg et al., 1994). A few investigators found a stronger protection among older women (Cramer et al., 1982; Beral et al., 1988), while others found lower risk among the young (Willett et al., 1981; Booth et al., 1989; Hartge et al., 1989).

Most of the results on the protection of OC on the risk of epithelial ovarian cancer are based on studies that have included women who have used the OC formulations introduced in the early 1960s with fixed and relatively high oestrogen and progestin doses. From the mid-1970s the hormone content in OC decreased. In the early 1980s the sequential OC compounds (biphasic and triphasic) were introduced. Only few studies have assessed these newer type OC formulations and epithelial ovarian cancer risk separately (CASH, 1987; Rosenblatt et al., 1992; Rosenberg et al., 1994). Ever use of one of two types of low dose OC (equal or less than 35 μg of ethinyl oestradiol) decreased the relative risk to 0.7 and 0.4, respectively (CASH, 1987), and sequential OC also reduced risk. Another study found a protective effect from both high-dose and low-dose OC formulations, the high-dose possibly being slightly more protective (Rosenblatt et al., 1992).

OC use seems to protect against all histological subtypes of epithelial ovarian tumours (Weiss et al., 1981; CASH, 1987), with the possible exception of mucinous tumours (Risch et al., 1996). Two studies have found a statistically non-significant risk increase for mucinous tumours among OC users (Cramer et al., 1982; WHO, 1989).

In conclusion, ever users of OC derive a 30% protection against epithelial ovarian cancer. Reduced risks are present across all strata of parity and age at diagnosis. The protection increases with duration of OC use with a 50% decline in risk after five years on the pill. The reduced risk persists for at least 10 years after cessation of use. As many women use OC, a positive health impact is evident. It is estimated that OC use averted approximately 1700 deaths from ovarian cancer in 1982 among US women aged 20–54 (CASH, 1987). In the choice of contraceptive method the positive effect of OC on epithelial ovarian cancer risk should be considered.

Progestin-only contraceptives

  1. Top of page
  2. Aetiology
  3. Age at menarche and menopause
  4. Parity and pregnancy
  5. Lactation
  6. Combined oral contraceptives
  7. Progestin-only contraceptives
  8. Hormone replacement therapy
  9. Infertility and ovulation induction
  10. Tubal ligation and hysterectomy
  11. Summary
  12. References

Information on progestin-only contraceptive methods in ovarian cancer epidemiology is limited. Daily intake of progestin-only pills prevents pregnancy through alterations of the cervical mucus and endometrium. Ovulatory cycles continue in a large proportion of women taking these formulations. Medroxyprogesterone acetate, as an injectable depot progestin, is given intramuscularly for contraception and in addition to cervical mucus and endometrial changes also prevents ovulation.

In a case–control series with 441 epithelial ovarian cancer patients and 2065 hospital control subjects, only one case and 22 control women had used the progestin-only pill for more than 3 years (Rosenberg et al., 1994). No risk estimates were given but the results seemed compatible with a protective effect. In another large study only one case and eight control women had taken progestin-only pills exclusively (CASH, 1987).

In a prospective study of 5000 women using injectable medroxyprogesterone acetate for contraception a relative risk of 0.8 (95% confidence interval 0.1–4.6) was found after 4–13 years of follow-up (Liang et al., 1983). The results were based on one observed vs. 1.16 expected cases after adjusting for those who were lost to follow-up.

The possible effect of both oral and injectable progestin-only contraceptives on the risk of epithelial ovarian cancer needs further evaluation.

Hormone replacement therapy

  1. Top of page
  2. Aetiology
  3. Age at menarche and menopause
  4. Parity and pregnancy
  5. Lactation
  6. Combined oral contraceptives
  7. Progestin-only contraceptives
  8. Hormone replacement therapy
  9. Infertility and ovulation induction
  10. Tubal ligation and hysterectomy
  11. Summary
  12. References

Hormone replacement therapy (HRT) efficiently relieves climacteric hot flushes and vasomotor symptoms. In the perimonopause it can be given to control bleeding irregularities. More recent indications include prophylaxis of osteoporosis and ischaemic heart disease (Barrett-Connor, 1992). There are international and temporal variations in the prevalence of HRT use. In a Finnish cross-sectional survey 20% of 45–64-year-old women were using HRT in 1989 (Topo et al., 1991). An increasing trend of use was reported from Rhode Island, US, from 1981 to 1990 (Derby et al., 1993). In the late 1970s the association between unopposed oestrogen use and endometrial cancer of the uterus became apparent (Ziehl, 1982). The adverse effect of unopposed oestrogens on endometrial cancer risk seems to be eliminated through the complementation of progestins (Persson et al., 1989; Voigt et al., 1991). In current HRT a medium potency oestrogen is usually supplemented with either a sequential or continuous progestin. After a hysterectomy unopposed oestrogens can still be used. Low potency oestrogens are used to treat vaginal atrophy and urogenital symptoms.

The results in epidemiology on HRT and the risk of epithelial ovarian cancer are inconsistent. Post-menopausal HRT decreases the secretion of pituitary gonadotrophins, although not to pre-menopausal levels (Larsson-Cohn et al., 1977). If the ‘gonadotrophin’ hypothesis applies to epithelial ovarian cancer a reduced risk is expected, unless a protection follows only with a more pronounced gonadotrophin suppression. Two studies have found HRT to protect against epithelial ovarian cancer (Smith et al., 1984; Hartge et al., 1988); in one (Hartge et al., 1988) a significant 40% risk reduction emerged. Most investigations have shown no association (West, 1966; Wynder et al., 1969; Annegers et al., 1977; Newhouse et al., 1977; Hildreth et al., 1981; Franceschi et al., 1982; Wu et al., 1988; Adami et al., 1989; Kaufman et al., 1989; Purdie et al., 1995). Also in a large combined analysis, no consistent relation between HRT and epithelial ovarian cancer risk appeared, but studies with population controls pointed to a slight increase in risk, while the opposite was found in studies with hospital controls (Whittemore et al., 1992). No increased risk of recurrent disease or ovarian cancer mortality was found with HRT after surgery for ovarian cancer (Eeles et al., 1991). Other studies indicate an increased risk of epithelial ovarian cancer with HRT (Hoover et al., 1977; Weiss et al., 1982; Cramer et al., 1983; Tzonou et al., 1984; Booth et al., 1989; Risch et al., 1996). In an Italian study a modest increase in odds ratio of 1.6 (95% confidence interval 1.2–2.6) was reported (Parazzini et al., 1994), while a stronger relationship with an odds ratio of 5.7 (95% confidence interval 1.1–30.8) was found in Greece (Polychronopoulou et al., 1993). Some studies point to an increased risk only for some histopathological subgroups of epithelial ovarian cancer; for instance, HRT appeared to increase risk of endometrioid tumours (LaVecchia et al., 1982; Weiss et al., 1982; Risch et al., 1996). It has been suggested that endometrioid ovarian cancers can be derived from endometriosis (Jiang et al., 1996). In a study on ovarian cancer mortality, HRT seemed to inflate the risk of fatal ovarian cancer, and risk increased with duration of HRT (Rodriguez et al., 1995). In most of the cited studies no clear trends with duration of HRT have emerged.

The question of whether HRT alters the risk of epithelial ovarian cancer remains unanswered. If an association exists, its relative magnitude probably is small. Nevertheless, it seems important to establish possible protective or adverse effects of HRT. As many women are exposed to HRT some years prior to the peak age-specific incidence of ovarian cancer, even a small change in relative risk can have a strong impact on the number of ovarian cancer cases. Almost all the reviewed studies have only considered women who have used unopposed medium potency oestrogens. Virtually no information exists on the role of oestrogen therapy supplemented by sequential or continuous progestins. Future research should clarify those issues and also investigate if the various subgroups of epithelial ovarian cancers are affected differently by HRT.

Infertility and ovulation induction

  1. Top of page
  2. Aetiology
  3. Age at menarche and menopause
  4. Parity and pregnancy
  5. Lactation
  6. Combined oral contraceptives
  7. Progestin-only contraceptives
  8. Hormone replacement therapy
  9. Infertility and ovulation induction
  10. Tubal ligation and hysterectomy
  11. Summary
  12. References

Nulliparity is an established risk factor for epithelial ovarian cancer. Central questions are if infertility and fertility drugs independently enhance risk. Major types of female infertility include tubal lesions, ovulatory disturbances and unexplained causes. Since the late 1960s the fertility drugs clomiphene citrate, hMG (human menopausal gonadotrophins) and hCG (human chorionic gonadotrophins) have been used to induce ovulation. Initial fertility drugs were given to anovulatory women, but with the development of assisted reproductive technology and IVF (in vitro fertilization), these drugs are now applied to many other types of infertility. If the ‘incessant ovulation’ hypothesis is true, ovulatory disturbances should decrease epithelial ovarian cancer risk, while infertility with ongoing ovulations may increase risk. In some types of ovulatory disturbances the levels of gonadotrophins are elevated and this could raise the risk if the ‘gonadotrophin’ hypothesis is true. After several case reports (Bamford & Steele, 1982; Bristow & Karlan, 1996), concern has been expressed that fertility drugs through high levels of gonadotrophins and excessive folliculogenesis could increase ovarian cancer risk (Fishel & Jackson, 1989).

In case–control studies it has been difficult to measure infertility accurately. Infertile women do not always seek medical advice, and even if they do are often unable to report the type of infertility. Definition of infertility has varied among studies. Physician-diagnosed infertility, self-reported infertility, periods of unprotected intercourse without becoming pregnant and time interval from marriage to the first birth are examples of infertility or subfertility definitions. These methodological concerns may explain some of the ambiguous results in attempts to answer if infertility has a separate effect from nulliparity on epithelial ovarian cancer risk. Infertility appeared to increase risk in most studies (Joly et al., 1974; McGowan et al., 1979; Hildreth et al., 1981; Cramer et al., 1983; Nasca et al., 1994; Ron et al., 1987; Hartge et al., 1988; Booth et al., 1989; Brinton et al., 1989; Whittemore et al., 1989, 1992; Risch et al., 1994; Rossing et al., 1994; Venn et al., 1995; Shushan et al., 1996). A few studies have found no such association (Kvåle et al., 1988; Franceschi et al., 1994). Infertility seems to carry a risk mainly in women who remain nulliparous, while temporary infertility periods among parous are free of risk (McGowan et al., 1979; Hartge et al., 1988; Booth et al., 1989; Chen et al., 1992; Whittemore et al., 1992). In a large Canadian case–control study, where most of the nulliparous women were so by choice, infertility did not appear to affect the risk for epithelial ovarian cancer among parous women, while a slightly elevated risk was seen in a small group of infertile nulliparous women (OR = 1.5, 95% confidence interval 0.6–4.1) (Risch et al., 1994). A recent investigation found infertility to significantly increase the risk of epithelial ovarian cancer among nulliparous women (OR = 2.5, 95% confidence interval 1.2–5.4) (Mosgaard et al., 1997).

Data on infertility types and ovarian cancer risk are derived from cohorts of women evaluated for infertility. The results are inconsistent, and due to a small number of ovarian cancer cases in the cohorts the risk estimates are imprecise. Non-hormonal infertility (RR = 3.2) and male infertility (RR = 6.7) were associated with the highest risk of ovarian cancer in an Israeli cohort (Ron et al., 1987). Hormonal abnormalities (RR = 1.6) and male infertility (RR = 2.0) were the highest risk categories in a cohort from Minnesota, USA (Brinton et al., 1989). Ovulatory abnormalities constituted the highest risk group (RR = 3.7) in a cohort in Seattle, USA (Rossing et al., 1994). In an Australian cohort of 10 358 women those with unexplained infertility had the highest risk estimates (RR = 19.2, 95% confidence interval 2.2–165), irrespective of treatment with fertility drugs (Venn et al., 1995).

In exploring the possible effect of fertility drugs on epithelial ovarian cancer risk, the key problem in case–control studies has been to find a suitable reference group. Also, it has been difficult to record valid fertility drug exposures. If women who have used fertility drugs are compared to the general population indication bias is likely to be introduced, as an apparent relation between fertility agents and ovarian cancer risk may be explained by infertility (the cause for treatment). Ideally the reference group should consist of infertile women not exposed to fertility drugs. Cohort studies have been hampered by small number of cancer cases, relatively short periods of follow-up and limited information on parity, OC use and other potential confounders.

In an Israeli cohort of 2632 women evaluated for infertility between 1964 and 1974, the intention was to analyse if a relation exists between fertility agents and risk for ovarian cancer in patients with hormonal infertility, but no conclusions could be drawn, as no cancer cases were observed in this group of the cohort versus one expected (Ron et al., 1987).

The results in the combined analysis of 12 US case–control studies brought attention to the possible relation between fertility drugs and ovarian cancer risk (Whittemore et al., 1992). Data on infertility and use of fertility drugs were available in three of the original studies. An increased risk for epithelial ovarian cancer was reported in infertile women treated with fertility drugs compared to women without infertility (OR = 2.8, 95% confidence interval 1.3–6.1). Women who stayed nulliparous after the use of fertility drugs had a much higher risk (OR = 27, 95% confidence interval 2.3–315.6) than women who became parous (OR = 1.4, 95% confidence interval 0.52–3.6). No clear patterns as to the role of infertility emerged. This study provoked criticism from several authors regarding selection bias, low validity of fertility drug exposures, temporal inconsistencies, confounding by infertility, wide confidence intervals and other methodological issues (Balasch & Barri, 1993; Cohen et al., 1993; Shapiro, 1995). Other authors have been supportive (Spirtas et al., 1993).

In a cohort of 3837 women evaluated for infertility in Seattle, US, 11 ovarian tumours were observed (four invasive, five borderline and two granulosa cell tumours) (Rossing et al., 1994). Compared to infertile unexposed women, infertile women who had taken clomiphene had a relative risk of 2.3 (95% confidence interval 0.5–11.4). In those who had used clomiphene for 12 or more monthly cycles the relative risk rose to 11.1 (95% confidence interval 1.5–82.3). The use of hCG did not appear to affect risk.

Interim results from an Italian case–control study indicate no increased risk with the use of fertility drugs (OR = 0.7, 95% confidence interval 0.2–3.3). In this study only two of 195 cases and 15 of 1339 control women have reported ever use of fertility drugs (Franceschi et al., 1994). In a Canadian case–control study with 1014 subjects, no cases and two controls had taken clomiphene (Risch et al., 1994).

Six ovarian cancer cases were detected in an Australian cohort of 10 358 women referred for infertility evaluation (Venn et al., 1995). Slightly elevated standardized incidence ratios (SIR) appeared both in 5564 women treated with fertility drugs (SIR = 1.7, 95% confidence interval 0.6–5.3) and in 4794 non-exposed women (SIR = 1.6, 95% confidence interval 0.5–5.0) when compared to age-standardized incidence rates in the general female population. Within-cohort comparisons between exposed and unexposed women showed a weak statistically non-significant risk increase with fertility drug use (SIR = 1.4, 95% confidence interval 0.3–7.6).

Results from an Israeli study with 200 cases (164 invasive and 36 borderline ovarian tumours) and 408 population controls suggested an increased risk with use of fertility drugs and particularly hMG (Shushan et al., 1996). Risk estimates were higher in women who had used hMG exclusively (OR = 3.2, 95% confidence interval 0.9–11.8) than in women who had taken any type of fertility drugs (OR = 1.3, 95% confidence interval 0.6–2.7).

In a recent nationwide case–control study from Denmark, after adjustment for parity and infertility, no excessive risk emerged for ovarian cancer with fertility drug use (Mosgaard et al., 1997). The risks of ovarian cancer among exposed compared to non-exposed infertile women were for nulliparous (OR = 0.8, 95% confidence interval 0.4–2.0) and for parous (OR = 0.6, 95% confidence interval 0.2–1.3), respectively. There was a statistically non-significant difference in age at diagnosis between stimulated (42.3 years) and non-stimulated (46.1 years) infertile cases. The dates of diagnosis were from 1989 to 1994 and data were collected through questionnaires sent to participants in 1994 and 1995. Of 1372 identified cases 513 (37%) had died and 684 (50%) provided data for analysis. The authors found no trends in risk factor prevalence according to year of diagnosis among cases, indicating that selection bias according to death unlikely distorted the odds ratios.

In summary, infertility adds to epithelial ovarian cancer risk in nulliparous women. Temporary fertility problems in parous women do not appear to raise risk. Current data do not allow a conclusion if fertility drugs independently affect risk. The association between fertility drugs and epithelial ovarian cancer risk emerging in several studies is not necessarily causal, but causality cannot be excluded. Women with refractory infertility most probably have the highest exposures to fertility drugs, but so far the separate effects of fertility drugs and infertility are not settled. As an increasing number of women are treated with fertility drugs in IVF programmes (Moosgard et al., 1997), it is prudent to design projects able to determine if a causal relationship between fertility drugs and ovarian cancer risk exists. Effects of the different fertility drugs, doses, number of cycles and latency have to be clarified. Any elevated risk has to be put into perspective with regard to attributable risks and to the protective effect of pregnancy as a result of fertility drug use. Can some preventive measure reduce risk among women with refractory infertility who seem to be in the highest risk category? Perhaps these women, after several failed IVF attempts, would benefit from OC use for some time, even if it precludes a potential pregnancy.

Tubal ligation and hysterectomy

  1. Top of page
  2. Aetiology
  3. Age at menarche and menopause
  4. Parity and pregnancy
  5. Lactation
  6. Combined oral contraceptives
  7. Progestin-only contraceptives
  8. Hormone replacement therapy
  9. Infertility and ovulation induction
  10. Tubal ligation and hysterectomy
  11. Summary
  12. References

Tubal ligation and hysterectomy are common gynecologic procedures, which appear to influence the risk of epithelial ovarian cancer. In most studies a reduced risk of epithelial ovarian cancer was found after tubal ligation (Hartge et al., 1988; Mori et al., 1988; Booth et al., 1989; Irwin et al., 1991; Whittemore et al., 1992; Hankinson et al., 1993; Risch et al., 1994; Rosenberg et al., 1994; Purdie et al., 1995; Rosenblatt et al., 1996; Miracle-McMahill et al., 1997). The risk reductions range from 10% to 80%. Data from the Nurses' Health Study cohort of 121 700 female nurses (30–55 years), followed from 1976 to 1988, indicated a 67% risk reduction (RR = 0.33, 95% confidence interval 0.16–0.64) after tubal ligation (Hankinson et al., 1993). The protection was present across all strata of parity. It has been suggested that detection bias may explain some of the protective effect, as ovaries that appear abnormal at surgery are removed (Weiss & Harlow, 1986). However, in the Nurses' Health Study the results were unchanged when the risk effect of baseline tubal ligation on ovarian cancer risk was estimated after excluding the ovarian cancer cases diagnosed during the first 4 years of follow-up. When surgery reports were reviewed only one of 260 observed cases were detected at surgery. In a study on mortality from ovarian cancer after tubal ligation the protective effect did not wane until 20 years after the procedure (Miracle-McMahill et al., 1971). A few studies did not find tubal ligation to protect against epithelial ovarian cancer (McGowan et al., 1979; Koch et al., 1988; Shu et al., 1989; Chen et al., 1992; Vessey et al., 1995). No studies have reported whether risk varies by method of tubal ligation, such as the Pomeroy or different laparoscopy techniques.

In a majority of studies hysterectomy seems to protect against epithelial ovarian cancer (Wynder et al., 1969; Joly et al., 1974; Annegers et al., 1979; McGowan et al., 1979; Cramer et al., 1982; Franceschi et al., 1982; Hartge et al., 1988; Irwin et al., 1991; Whittemore et al., 1992; Hankinson et al., 1993; Parazzini et al., 1993; Risch et al., 1994; Rosenberg et al., 1994; Purdie et al., 1995; Rosenblatt et al., 1996). The risk reduction following hysterectomy is probably less pronounced than that after tubal ligation. For example, in the Nurses' Health Study hysterectomy reduced risk by 33% (RR = 0.67, 95% confidence interval 0.45–0.99). Some studies have not found hysterectomy to be protective (Newhouse et al., 1977; Casagrande et al., 1979; Hildreth et al., 1981).

The mechanism by which tubal ligation and hysterectomy reduce epithelial ovarian cancer risk is speculative. The ovaries receive arterial blood from the ovarian arteries and from the ovarian branches of the uterine arteries, which run parallel to the Fallopian tubes. At hysterectomy the ovarian branches of the uterine arteries are divided and immediate reductions in ovarian blood flow have been measured (Janson & Jansson, 1977). It is also suspected that blood flow in the ovarian branches of the uterine arteries may cease as a result of extensive tissue damage at tubal ligation, resulting in decreased ovarian hormone production. Reductions in oestrogen and progesterone levels have been reported after tubal ligation (Donnez et al., 1981; Radwanska et al., 1982; Cattanach & Milne, 1988), findings not confirmed by others (Alvarez-Sanchez et al., 1981; Corson et al., 1981; Sörensen et al., 1981; Helm & Sjöberg, 1983). Lower levels of LH after tubal ligation have been reported in one study (Alvarez-Sanchez et al., 1981), but not in others (Sörensen et al., 1981; Radwanska et al., 1982). Ovulatory cycles were reported to continue after hysterectomy (Doyle et al., 1971). Reduced progesterone levels may reflect anovulation, and according to the ‘incessant’ ovulation hypothesis could explain the reduced risk after tubal ligation and hysterectomy. On the contrary, if ovarian oestrogen and progesterone production decreases, the gonadotrophin secretion may be expected to rise, leading to an increased risk if the ‘gonadotrophin’ hypothesis is true. None of the hypotheses receive consistent support by the conflicting results from studies on hormone levels after tubal ligation or hysterectomy. An alternate explanation for the reduced risk is an interrupted retrograde transport of potential endogenous or exogenous carcinogens through the Fallopian tubes (Cramer & Xu, 1995). This explanation gains support in the high frequency of retrograde menstrual flow (Halme et al., 1984).

In summary, tubal ligation and hysterectomy appear to protect against epithelial ovarian cancer. As many women have had one of these procedures a considerable number of epithelial ovarian cancers may be prevented. When recommending contraceptive methods the positive effect of tubal ligation on the risk of epithelial ovarian cancer should be considered. The cause of the protective effect remains unclear.

Summary

  1. Top of page
  2. Aetiology
  3. Age at menarche and menopause
  4. Parity and pregnancy
  5. Lactation
  6. Combined oral contraceptives
  7. Progestin-only contraceptives
  8. Hormone replacement therapy
  9. Infertility and ovulation induction
  10. Tubal ligation and hysterectomy
  11. Summary
  12. References

Epithelial ovarian cancer is fairly common with high rates in Scandinavia, intermediate rates in western Europe and North America and low rates in the developing countries and in Japan. The 5-year survival rate is less than 40%. Increasing parity consistently gives a strong protection against epithelial ovarian cancer. A lesser degree of protection is probably derived from incomplete pregnancies and lactation. Ages at menarche and menopause are most probably weak predictors of epithelial ovarian cancer risk. Ever users of oral contraceptives (OC) have 30% lower risk compared to never users. The protection increases with duration of OC use, being about 50% after 5 years. The reduced risk among past OC users persists for at least 10 years after cessation of use. Results concerning hormone replacement therapy (HRT) and epithelial ovarian cancer risk are conflicting, but most data point to a weak or no association, but as an increasing number of women use HRT it still seems important to resolve any potential effect. Infertility adds to epithelial ovarian cancer risk in nulliparous women, while temporary fertility problems in parous women do not appear to increase risk. A possible independent risk effect of fertility drug use has not been easy to assess and remains unresolved. It has been particularly difficult to separate the effects of fertility drugs from those of infertility. Tubal ligation and hysterectomy convey protection against epithelial ovarian cancer, possibly through a suppressed ovarian hormone production.

The causes of epithelial ovarian cancer are poorly understood, but reproductive hormones are thought to be involved in the aetiology. For a long time the ‘incessant’ and ‘gonadotrophin’ hypotheses have been promoted in relation to carcinogenesis. Both hypotheses find support in ovarian cancer epidemiology, and recent progress in molecular biology adds to the understanding of possible aetiological mechanisms. Another hypothesis focuses on the retrograde transport of contaminants or carcinogens through the Fallopian tubes. It is important to establish if the same risk factors apply to the various histological types of ovarian cancer, as particularly the mucinous ovarian tumours seem to present with different risk factors. Another question to resolve is if sporadic vs. inherited cases carry distinct risk profiles. As the hypotheses above do not explain all of the results derived from ovarian cancer epidemiology, there is a need to test additional hypotheses to possibly define preventive programmes and to come closer to the cause of ovarian cancer.

References

  1. Top of page
  2. Aetiology
  3. Age at menarche and menopause
  4. Parity and pregnancy
  5. Lactation
  6. Combined oral contraceptives
  7. Progestin-only contraceptives
  8. Hormone replacement therapy
  9. Infertility and ovulation induction
  10. Tubal ligation and hysterectomy
  11. Summary
  12. References
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