Hormonal aspects of epithelial ovarian cancer: review of epidemiological evidence

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. 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., et al., but not by et al., In a case–control study women with had an increased risk of developing epithelial ovarian (Schildkraut et al., with have an elevated stimulating In a study levels were found among women developed ovarian cancer, a that the ‘gonadotrophin’ hypothesis et al., 1995). age at and late age at increase the number of ovulatory cycles and in the years may be In support of the ‘incessant ovulation’ hypothesis, an early age at and a late age at increase the risk of epithelial ovarian the a late age at the risk in post-menopausal gonadotrophins and possibly risk to the have the and the risk of epithelial ovarian A number of studies have found a risk increase with at a in studies from to when years with more than years of and are not et al., et al., 1988; et al., et al., et al., 1993; et al., et al., 1995). In a a from epithelial ovarian cancer was found with late age at and in study population was common with years of age et al., 1989). In studies the age at and epithelial ovarian cancer risk et al., et al., et al., et al., et al., 1988; et al., 1991; et al., 1993). study showed a increased risk with late age at et al., A age at and ovarian cancer risk was found in several case–control with risk studies from to for the et al., et al., et al., 1988; et al., et al., et al., et al., 1991; et al., 1993). The increased risk from late also among women et al., 1989). age at and ovarian cancer risk was found in et al., 1988; et al., 1995) and case–control studies et al., et al., et al., et al., et al., et al., 1988; et al., 1992). The results among studies that age at and are most of ovarian cancer The of and in epidemiological studies be to and which may some of the a late age at may increase the risk of ovarian to and of pituitary In with both the ‘incessant ovulation’ and the ‘gonadotrophin’ is to the risk of epithelial ovarian of the most in ovarian cancer is the effect of on epithelial ovarian cancer risk et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., 1988; et al., 1988; et al., 1988; et al., 1988; et al., et al., et al., et al., et al., 1991; et al., et al., et al., 1993; et al., 1993; et al., & et al., et al., women to have risk in the of et al., et al., et al., 1988; et al., et al., 1991; et al., et al., 1993). In a of case–control studies a risk was found for the and the risk et al., 1992). A risk with with a risk of for or more was in a study et al., 1988). of was also found in a case–control study in a of with a of (Adami et al., 1994). In a risk from to the while not risk et al., In a et al., a and age from ovarian cancer in countries and for in the and A of investigators have found a or and ovarian cancer risk et al., et al., 1993). In a recent study a risk was associated with among BRCA1 carriers (Narod et al., 1995). The influence of age at on epithelial ovarian cancer risk is case–control studies with have shown a with age at et al., et al., et al., et al., et al., et al., et al., 1991; et al., et al., 1993; et al., 1993). In the case–control study in a of a risk for 5-year in age at and was also found that the effect of with (Adami et al., 1994). A risk with late age at also has been in some case–control studies with population et al., et al., 1993; et al., in et al., effect was to women A found a effect from late age at for women et al., reflect age at and epithelial ovarian cancer risk et al., et al., et al., et al., et al., et al., et al., et al., et al., 1988; et al., 1988; et al., 1988; et al., et al., et al., et al., et al., 1995). The role of on epithelial ovarian cancer risk also The of differ among and are at are an increased number of many investigators have found a effect on ovarian cancer risk et al., et al., et al., et al., 1988; et al., 1988; et al., et al., et al., et al., et al., 1993). the risk is and is not In studies of was found et al., et al., et al., et al., et al., 1988; et al., et al., et al., 1993; et al., et al., 1995). showed a increased epithelial ovarian cancer risk with or more et al., et al., were found in several studies et al., 1988; et al., 1988; et al., et al., et al., 1992). Other investigators not find an altered risk with et al., 1993; et al., et al., Spontaneous risk in study et al., and not risk in et al., 1988; et al., et al., 1989). risk with in some et al., et al., et al., the epidemiological the effect of on the risk of epithelial ovarian cancer is The effect of age at is not but case–control studies with population and that a age at epithelial ovarian cancer also not as as The reproductive are and in may to the of and some of the results among and of is the of pituitary and to especially in the the ‘incessant ovulation’ and ‘gonadotrophin’ hypotheses are be to the risk of epithelial ovarian studies have found a risk with et al., et al., 1988; et al., et al., et al., et al., 1993; et al., 1994). The of the risk is with and with of are the to be more than at Other studies have found and epithelial ovarian cancer risk et al., et al., et al., et al., et al., 1995). In studies with a risk increase was found et al., 1988; et al., 1989). the the is that epithelial ovarian cancer, especially both and The effect from a gonadotrophin and inhibited to the and hypotheses is to the risk of epithelial ovarian In ovarian cancer is evidence that cancer from of has in a majority of studies et al., et al., et al., et al., et al., et al., et al., et al., et al., 1991; et al., et al., et al., et al., 1988; et al., 1988; et al., et al., et al., 1991; et al., et al., et al., 1993; et al., et al., et al., et al., & 1995). A studies from the and the a risk of for of et al., 1992). study found and epithelial ovarian cancer risk et al., 1989). The is a case–control where an of was found et al., 1989). of to increase the epithelial ovarian In most studies a risk related to several years of et al., et al., et al., et al., et al., et al., et al., 1988; et al., 1988; et al., et al., 1991; et al., et al., 1993; et al., et al., et al., et al., & 1995). studies that may to a risk (Cramer et al., et al., et al., 1992). In a review a risk was years on the 1991). A was in a et al., with of to the risk The effect of to for a the of A risk when at years had (Cramer et al., et al., et al., et al., et al., 1994). In some studies a risk of years the et al., et al., 1991; et al., 1994). increased risk with of is reported in study et al., 1989). to epithelial ovarian cancer of In the a risk of was found for both and women et al., 1992). effect of on the and epithelial ovarian cancer may A among women was found in some studies et al., et al., et al., while the in et al., et al., et al., et al., et al., & 1995). The of on epithelial ovarian cancer risk to be present at at et al., et al., 1988; et al., et al., 1991; et al., 1994). studies that risk by not with age et al., 1994). A investigators found a among women (Cramer et al., et al., while found risk among the et al., et al., et al., 1989). of the results on the of on the risk of epithelial ovarian cancer are on studies that have women have the in the early with and high oestrogen and the the hormone in In the early the and were studies have type and epithelial ovarian cancer risk et al., et al., 1994). of of types of low or less than of the risk to and and also study found a effect from both and the possibly more et al., 1992). to of epithelial ovarian tumours et al., with the possible of mucinous tumours et al., studies have found a risk increase for mucinous tumours among (Cramer et al., 1989). In of a epithelial ovarian are present of and age at The increases with of with a in risk years on the The risk for at years of As many women a is is estimated that approximately from ovarian cancer in among women In the of the effect of on epithelial ovarian cancer risk be on in ovarian cancer is of through of the and cycles in a of women as an is for and in to and also In a case–control with epithelial ovarian cancer and and women had the for more than years et al., 1994). risk were but the results with a In study and women had In a study of women for a risk of was found years of et al., 1983). The results were on cases for were to The possible effect of both and on the risk of epithelial ovarian cancer replacement and In the be to recent of and disease 1992). There are and in the prevalence of In a of women were in et al., 1991). of was reported from from to et al., 1993). In the late the oestrogen and cancer of the The effect of on cancer risk to be through the of et al., et al., 1991). In a oestrogen is with a or a still be are to and The results in on and the risk of epithelial ovarian cancer are the of pituitary not to levels et al., the ‘gonadotrophin’ hypothesis to epithelial ovarian cancer a risk is a with a more gonadotrophin studies have found to epithelial ovarian cancer et al., et al., in et al., a risk have shown et al., et al., et al., et al., et al., et al., 1988; et al., et al., et al., 1995). in a and epithelial ovarian cancer risk but studies with population to a increase in while the was found in studies with et al., 1992). increased risk of disease or ovarian cancer was found with for ovarian cancer et al., 1991). Other studies an increased risk of epithelial ovarian cancer with et al., et al., et al., et al., et al., et al., In an study a increase in of was reported et al., while a with an of was found in et al., 1993). studies to an increased risk for some histopathological subgroups of epithelial ovarian for to increase risk of tumours et al., et al., et al., has been that ovarian cancers be derived from et al., In a study on ovarian cancer to the risk of ovarian cancer, and risk increased with of et al., 1995). In most of the studies clear with of have The of the risk of epithelial ovarian cancer an its is to possible or of As many women are exposed to some years to the age-specific incidence of ovarian cancer, a in risk have a on the number of ovarian cancer the studies have women have on the role of oestrogen by or and also the subgroups of epithelial ovarian cancers are by is an risk factor for epithelial ovarian are infertility and types of infertility ovulatory and the late the and have been to were to but with the development of reproductive and vitro are to many types of the ‘incessant ovulation’ hypothesis is ovulatory epithelial ovarian cancer while infertility with may increase In some types of ovulatory the levels of gonadotrophins are elevated and the risk the ‘gonadotrophin’ hypothesis is several & & has been that through high levels of gonadotrophins and increase ovarian cancer risk & 1989). In case–control studies has been to infertility women not and are to report the type of of infertility has among of and from to the are of infertility or These may some of the results in to infertility has a effect from on epithelial ovarian cancer to increase risk in most studies et al., et al., et al., et al., et al., et al., et al., 1988; et al., et al., et al., et al., et al., et al., et al., A studies have found et al., 1988; et al., 1994). to a risk in women while infertility among are of risk et al., et al., 1988; et al., et al., et al., 1992). In a case–control where most of the women were by infertility not to the risk for epithelial ovarian cancer among while a elevated risk was in a of women et al., 1994). A recent found infertility to significantly increase the risk of epithelial ovarian cancer among women et al., 1997). on infertility types and ovarian cancer risk are derived from of women for The results are and to a number of ovarian cancer cases in the the risk are infertility and infertility were associated with the risk of ovarian cancer in an et al., and infertility were the risk in a from et al., 1989). the risk in a in et al., 1994). In an of women with infertility had the risk of treatment with et al., 1995). In the possible effect of on epithelial ovarian cancer the in case–control studies has been to find a has been to women have are to the general population is to be as an and ovarian cancer risk may be by infertility for the of women not exposed to studies have been by number of cancer of and on and potential In an of women for infertility and the was to a and risk for ovarian cancer in with hormonal but be as cancer cases were in of the et al., The results in the of case–control studies to the possible and ovarian cancer risk et al., 1992). on infertility and of were in of the increased risk for epithelial ovarian cancer was reported in women with to women infertility the of had a risk than women clear as to the role of infertility This study from several low of by and & 1993; et al., 1993; 1995). Other have been et al., 1993). In a of women for infertility in ovarian tumours were borderline and cell et al., 1994). to women had had a risk of In had for or more cycles the risk to The of not to results from an case–control study increased risk with the of In study of cases and of women have reported of et al., 1994). In a case–control study with cases and had et al., 1994). ovarian cancer cases were in an of women for infertility et al., 1995). elevated incidence both in women with and in women when to incidence rates in the general exposed and women showed a risk increase with from an study with cases invasive and borderline ovarian and population an increased risk with of and et al., were in women had than in women had type of In a recent case–control study from for and risk for ovarian cancer with et al., 1997). The of ovarian cancer among exposed to women were for and for There was a in age at stimulated and The of were from to 1994 and were through to in 1994 and Of identified cases had and for The found in risk factor prevalence to of among indicating that to the In infertility to epithelial ovarian cancer risk in women. in women not to not a The and epithelial ovarian cancer risk in several studies is not but be with infertility most have the to but the of and infertility are not As an number of women are with in et al., 1997), is to to a and ovarian cancer risk of the number of cycles and have to be elevated risk has to be into with to and to the effect of as a of some risk among women with infertility seem to be in the risk several from for some a potential and are common which to influence the risk of epithelial ovarian In most studies a risk of epithelial ovarian cancer was found et al., 1988; et al., 1988; et al., et al., 1991; et al., et al., 1993; et al., et al., et al., et al., et al., 1997). The risk from to from the of from to a risk et al., 1993). The was present of has been that may some of the as ovaries that at are & in the the results were when the risk effect of on ovarian cancer risk was estimated the ovarian cancer cases diagnosed the years of were of cases were at In a study on from ovarian cancer the effect not years the et al., A studies not find to epithelial ovarian cancer et al., et al., 1988; et al., et al., et al., 1995). studies have reported risk by of as the or In a majority of studies to epithelial ovarian cancer et al., et al., et al., et al., et al., et al., et al., 1988; et al., 1991; et al., et al., 1993; et al., 1993; et al., et al., et al., et al., The risk is less than that For in the risk by studies have not found to be et al., et al., et al., The by which and epithelial ovarian cancer risk is The ovaries from the ovarian and from the ovarian of the which to the Fallopian tubes. the ovarian of the are and in ovarian have been & is also that in the ovarian of the may as a of damage at in ovarian hormone in oestrogen and progesterone levels have been reported et al., et al., & not by et al., et al., et al., & 1983). levels of have been reported in study et al., but not in et al., et al., cycles were reported to et al., progesterone levels may reflect and to the hypothesis the risk and the ovarian oestrogen and progesterone production the gonadotrophin may be to to an increased risk the ‘gonadotrophin’ hypothesis is of the hypotheses support by the results from studies on hormone levels or for the risk is an retrograde transport of potential endogenous or carcinogens through the Fallopian (Cramer & Xu, 1995). This support in the high of retrograde et al., In and to epithelial ovarian As many women have had of a number of epithelial ovarian cancers may be the effect of on the risk of epithelial ovarian cancer be The of the effect Epithelial ovarian cancer is common with high rates in intermediate rates in western Europe and America and low rates in the developing countries and in The 5-year survival is less than 40%. a epithelial ovarian A of is derived from and at and are most of epithelial ovarian cancer of have risk to The increases with of The risk among for at years of hormone replacement and epithelial ovarian cancer risk are but most to a or but as an number of women still to potential to epithelial ovarian cancer risk in while in women not to increase A possible risk effect of has not been to and unresolved. has been to the of from of and epithelial ovarian cancer, possibly through a ovarian hormone The causes of epithelial ovarian cancer are poorly but reproductive hormones are thought to be involved in the aetiology. For a the and ‘gonadotrophin’ hypotheses have been in to carcinogenesis. hypotheses find support in ovarian cancer and recent progress in molecular biology to the of possible aetiological hypothesis on the retrograde transport of contaminants or carcinogens through the Fallopian tubes. is to the risk factors to the types of ovarian cancer, as the mucinous ovarian tumours seem to present with risk to is sporadic inherited cases risk As the hypotheses not of the results derived from ovarian cancer is a to hypotheses to possibly and to to the of ovarian