Risk for borderline ovarian tumours after exposure to fertility drugs: results of a population-based cohort study.
OBJECTIVE
Do fertility drugs increase the risk for borderline ovarian tumours, overall and according to histological subtype?


CONCLUSIONS
The use of any fertility drug did not increase the overall risk for borderline ovarian tumours, but an increased risk for serous borderline ovarian tumours was observed after the use of progesterone.


BACKGROUND
Many epidemiological studies have addressed the connection between fertility drugs use and risk for ovarian cancer; most have found no strong association. Fewer studies have assessed the association between use of fertility drugs and risk for borderline ovarian tumours, and the results are inconsistent.


METHODS
A retrospective case-cohort study was designed with data from a cohort of 96 545 Danish women with fertility problems referred to all Danish fertility clinics in the period 1963-2006. All women were followed for first occurrence of a borderline ovarian tumour from the initial date of infertility evaluation until a date of migration, date of death or 31 December 2006, whichever occurred first. The median length of follow-up was 11.3 years.


METHODS
Included in the analyses were 142 women with borderline ovarian tumours (cases) and 1328 randomly selected sub-cohort members identified in the cohort during the follow-up through 2006. Cases were identified by linkage to the Danish Cancer Register and the Danish Register of Pathology by use of personal identification numbers. To obtain information on use of fertility drugs, hospital files and medical records of infertility-associated visits to all Danish fertility clinics were collected and supplemented with information from the Danish IVF register. We used case-cohort techniques to calculate rate ratios (RRs) and corresponding 95% confidence intervals (CIs) for borderline ovarian tumours, overall and according to histological subtype, associated with the use of any fertility drug or five specific groups of fertility drugs: clomiphene citrate, gonadotrophins (human menopausal gonadotrophins and follicle-stimulating hormone), gonadotrophin-releasing hormone analogues, human chorionic gonadotrophins and progesterone.


RESULTS
Analyses within the cohort showed that the overall risk for borderline ovarian tumours was not associated with the use of any fertility drug (RR 1.00; 95% CI 0.67-1.51) or of gonadotrophins (RR 1.32; 95% CI 0.81-2.14), clomiphene citrate (RR 0.96; 95% CI 0.64-1.44), human chorionic gonadotrophins (RR 0.91; 95% CI 0.61-1.36) or gonadotrophin-releasing hormone analogues (RR 1.10; 95% CI 0.66-1.81). Furthermore, no associations were observed between the risk for borderline ovarian tumours and these groups of fertility drugs according to the number of cycles of use, length of follow-up or parity. In contrast, use of progesterone increased the risk for borderline ovarian tumours, particularly serous tumours, for which statistically significantly increased risks were observed with any use of progesterone (RR 1.82; 95% CI 1.03-3.24), among women treated with ≥4 cycles of progesterone (RR 2.63; 95% CI 1.04-6.64) and for all women followed up for ≥4 years after their first treatment with progesterone.


CONCLUSIONS
Although we tried to minimize the effects of the underlying infertility, the severity of infertility might have affected our risk estimates, as women with more severe fertility problems may receive more treatment. The results from the subgroup analyses, e.g. the findings of an elevated risk for borderline ovarian tumours associated with increased time since first use of progesterone and with increased number of treatment cycles, should be interpreted with caution as these analyses are based on a limited number of women with borderline ovarian tumours.


CONCLUSIONS
Although this study, which is the largest to date, provides reassuring evidence that there is no strong link between the use of fertility drugs and risk for borderline ovarian tumours, the novel observation of an increased risk for serous tumours after use of progesterone should be investigated in large epidemiological studies. The results of the present study provide valuable knowledge for clinicians and other health care personnel involved in the diagnosis and treatment of fertility problems.


BACKGROUND
No conflict of interest was reported. S.M.B. was supported by a research scholarship from the Danish Cancer Society.
Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen Ø, Denmark.
Sarah Marie
SM
Bjørnholt
Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen Ø, Denmark Department of Gynaecology, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen Ø, Denmark.
Susanne Krüger
SK
Kjaer
Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen Ø, Denmark.
Thor Schütt Svane
TS
Nielsen
Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen Ø, Denmark allan@cancer.dk.
Allan
A
Jensen
D005260:Female; D005300:Fertility Agents, Female / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D010051:Ovarian Neoplasms / Q000453:epidemiology* / Q000473:pathology; D011374:Progesterone / Q000009:adverse effects* / Q000627:therapeutic use; D012189:Retrospective Studies; D012307:Risk Factors
D005300:Fertility Agents, Female; D011374:Progesterone
Denmark; borderline ovarian tumours; fertility drugs; infertility; population-based cohort study