Discussion
This literature review has not determined any clear correlation between hormonal infertility treatment used in the context of assisted fertilisation and an elevated risk of cancer of the breast, the uterus or the cervix. Since many of the women who have undergone hormonal infertility treatment are still relatively young, many years will pass until they reach the age where the incidence of cancer is at its highest. A general feature of the studies included was a low number of cancer cases. Several studies showed a trend towards an elevated risk following infertility treatment. Despite the large cohorts, the number of women who developed cancer was too low to achieve significant results. This demonstrates the need for larger studies and meta-analyses that can provide more precise results. It is also worth bearing in mind that epidemiological studies cannot provide any specific conclusions regarding the cause of the development of cancer. Other factors associated with both infertility and cancer, such as overweight (37, 38), may also play a role. Infertility in general, as well as causes of infertility, such as endometriosis (39, 40), ovulatory disorders, polycystic ovary syndrome (37, 41) and tubal factors (42, 43) may also have an effect on the risk of developing cancer in the breast, the ovaries or the uterus.
The hormonal treatment exposes the women to supraphysiological concentrations of exogenous hormones, causing an increase in the concentrations of oestrogen and progesterone that may possibly contribute to an elevated risk of breast cancer. Most of the studies we reviewed in Table 1 showed that there was no elevated risk of breast cancer associated with infertility treatment, although one of the studies, (a case-control study) (18), concluded that women who underwent IVF treatment after the age of 30 were diagnosed with cancer at an earlier time (average age 43.9) than women in the general population, who in this study were aged 60 on average at the time of diagnosis. One study indicated that IVF treatment protects women against breast cancer (14). On the other hand, some of the studies reviewed show an elevated risk of breast cancer, especially following treatment with clomiphene citrate and 20 years of follow-up (16), gonadotropin (21) and progesterone (17). Again, however, the results are unconvincing and the evidence is not clear.
Treatment with clomiphene citrate and gonadotropins in the context of assisted fertilisation stimulates follicle maturation and induces ovulation. The ovulation may in itself be part of mechanisms associated with ovarian-cancer aetiology (44, 45). The hypothesis of incessant ovulation (45) postulates that frequent ovulation causes damage to and repair of the surface epithelium of the ovary and increases the likelihood of DNA mutations and may generate a predisposition for malign transformation (4). This may explain why multiparous women have a risk of ovarian cancer which is 30 – 70 % lower than in nulliparous women (46) – (48).
In their study, Källén and collaborators (14) describe the risk of cancer in women who have given birth after IVF treatment. Their control group consisted of women who had given birth with no IVF treatment. They detected an elevated risk of cancer, especially ovarian cancer, in the IVF women both before and after pregnancy/delivery. However, the cancer risk was somewhat reduced after delivery. A possible explanation could be that pathologies of the ovaries may be the cause of the infertility as well as the elevated risk of ovarian cancer. Jensen and collaborators draw the same conclusion in their studies of a cohort of 54 362 women (26, 49). A study from the Netherlands published in 2011 (30) and a study from Sweden published in 2009 (31) assessed the risk of borderline ovarian tumours and invasive ovarian cancer, and reported a possible elevated risk of borderline tumours of the ovaries and also a possible elevated risk of invasive ovarian cancer after treatment with gonadotropin (31). It is important to underscore that borderline ovarian tumour is essentially a benign disease with a low likelihood of malignancy. We have nevertheless chosen to include this finding in Table 2, since it will be important to the women concerned. The conventional treatment for this condition includes bilateral oophorectomy and hormone replacement.
Despite the large cohorts of women who receive in-vitro fertilisation, only a small number of women develop cancer, and the studies are based on small numbers. This calls for continued monitoring of the long-term effects of hormonal stimulation in the context of infertility treatment with regard to the risk of development of invasive ovarian cancer and borderline tumours.
After 30 years of follow-up, Lerner-Geva and collaborators detected a significant increase in the incidence of endometrial cancer in women who had been treated with clomiphene citrate and hMG (11). One study describes a temporarily elevated risk of uterine cancer during the first year after a completed ovulation induction, especially among women suffering from unexplained infertility (22). Several studies concluded that infertility treatment with clomiphene citrate, hMG, gonadotropin and gonadotropin-releasing hormone analogues may give rise to an elevated risk of uterine cancer (6, 11, 21, 34, 35), while others failed to detect any elevated risk (7, 8, 13, 14). There was no expected elevated risk of cervical cancer after treatment of infertility with the aid of exogenous hormones. This was also the conclusion in all the studies reviewed (Table 4). However, a reduced risk of cervical cancer was reported by two studies (13, 14). A possible explanation could be that women who undergo treatment of infertility have more frequent gynaecological examinations, and are thus treated for cell atypia in the cervix at an earlier stage (13).