European Journal of Obstetrics & Gynecology and Reproductive Biology
ReviewDoes fertility treatment increase the risk of uterine cancer? A meta-analysis
Introduction
An ongoing debate over the last two decades has focused on whether the treatment of infertility in women may lead to cancer involving the uterus (uterine, endometrial or cervical cancer) over a period of time.
Currently 1 in 7 couples in the UK are affected by infertility [1]. This has resulted in an year on year increase in the use of fertility treatments [2]. These treatments may involve the use of ‘stand-alone’ medications, for example, anti-oestrogens such as clomiphene citrate (CC) and less frequently tamoxifen for ovulation induction. Fertility treatments may also be part of in vitro fertilization (IVF) cycles including the use of human menopausal gonadotropins (hMG), recombinant follicle-stimulating hormone (rFSH) and human chorionic gonadotropins (hCG).
Uterine cancer (including mainly endometrial carcinoma and the less common uterine sarcoma) is the commonest reproductive tract cancer and the fourth commonest cancer in women in the UK with 6834 new cases diagnosed in 2010 [3]. Risk factors for endometrial cancer can be split into two groups, endogenous such as a strong family history, increasing age (with 60 being the average age), polycystic ovarian syndrome (PCOS) and obesity; and exogenous, such as unopposed oestrogen and tamoxifen therapy and previous radiotherapy [4].
Fertility treatment often results in increased and unopposed supra-physiological levels of oestradiol. This exogenous risk factor may lead to endometrial hyperplasia, a premalignant condition that can predispose to atypical complex endometrial hyperplasia and therefore ultimately lead to endometrial cancer itself. The risk of uterine malignancy may also apply to simple fertility medications such as Tamoxifen as reported previously [5]. This is of a specific concern with regards to cases of anovulatory infertility, a large number of which are linked to PCOS [6]. While unexplained infertility has been associated with a later diagnosis of uterine cancer [7], patients with primary infertility secondary to anovulation seemed also to be particularly predisposed to developing uterine cancers. Brinton et al. reported a RR of 2.42 (95% CI: 1.0–5.8). However, in this study, only 5% of women were classified as PCOS [8]. Recently, Barry et al. published a meta-analysis which showed that women of all ages with PCOS are at an increased risk of endometrial cancer. The risk of ovarian and breast cancer however was not significantly increased overall. These results highlight the potential risk of gynaecological cancer morbidities associated with PCOS [9].
A review of the literature demonstrates that the effect of fertility treatment has been reported mainly with respect to ovarian and breast cancers, but not uterine cancer.
This meta-analysis of retrospective studies is aimed at assessing the association, if any, between fertility treatment used both as an independent therapy as well as during IVF cycles, and the development of uterine cancer following that treatment.
Section snippets
Materials and methods
The meta-analysis was done according to PRISMA guidelines. A literature search was performed using Medline, Embase, the Cochrane Library and Google Scholar databases for comparative studies until September 2014 to investigate a clinical significance of carrying out fertility treatment on the incidence of developing uterine cancer in the future. The following MESH search headings were used: fertility agents, infertility; female, infertility treatment, uterus, uterine, endometrial, sarcoma,
Results
We initially identified 32 studies using the literature search criteria previously described. Eight studies, all of which were published between 1998 and 2014, were selected for the meta-analysis [7], [16], [17], [18], [19], [20], [21], [22], [23], according to the stated selection criteria. One study was then excluded, because the incidence of uterine cancer following fertility treatment could not be calculated from the published results [22]. Another study was excluded because of the
Comment
It is today's rapid increase in the rate of ovarian stimulation in a patient with a history of either anovulation or minimal ovulation which has led fertility centres to investigate over the last few decades whether a possible association between the exposure to fertility treatments and cancer development exists [8], [24], [25], [26].
The most important mechanism leading to the development of uterine cancer is the excessive exposure to both endogenous and exogenous oestrogens [27]. Therefore,
Conclusion
The risk for the development of uterine and in particular endometrial cancer posed by infertility and an unopposed oestrogen state is widely recognized. The present analysis aimed to perceive whether standard fertility drugs were also a risk to future uterine cancer development. The treatment does increase the concentrations of unopposed oestrogen for a short periods of time but if successful leads to fertility. This meta-analysis points to a non-deleterious effect of fertility drugs towards
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Development of endometrial stromal sarcoma in a patient undergoing in vitro fertilization: A case report
2020, Gynecologic Oncology ReportsCitation Excerpt :A study by Venn et al found an increased incidence of uterine sarcoma (two cases of stromal sarcoma, two cases of leiomyosarcomas) between one and twelve years after receiving IVF treatment (Venn et al., 2001). However, there have been multiple meta-analyses that have not demonstrated a statistically significant increased risk of these malignancies (Schwarze et al., 2017; Saso et al., 2015). Although it has been established that hormonal therapies may be associated with the progression of ESS specifically, to date, an association with IVF and the effect of fertility treatments on disease progression have not been described.
Long-Term Cardiovascular Morbidity in Children Born Following Fertility Treatment
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2018, Encyclopedia of Endocrine DiseasesFertility treatments and pediatric neoplasms of the offspring: results of a population-based cohort with a median follow-up of 10 years
2017, American Journal of Obstetrics and GynecologyCitation Excerpt :The association between fertility treatment and malignancy risks has been studied previously for both mothers and their conceived offspring. Although among mothers, most recent studies found no associations between IVF treatments and cancer19-21; among the offspring, results were less consistent. Several studies, which included metaanalyses, have found an overall increase in childhood cancers after fertility treatments6,22,23; other studies have not found such an association,24-29 although most of these studies have found an association with certain cancer types (including Hodgkin’s lymphoma, leukemia, central nervous system tumors).24,27-30
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S. Saso and L. Louis are joint 1st authors.