Description of the condition

The prevalence of subfertility in Western societies ranges from 3% to 33% (Boivin 2007; Chandra 1998; Greenhall 1990; Healy 1994; Karmaus 1999; Schmidt 1995). It is reported that in the UK one in seven heterosexual couples suffer from subfertility (NICE 2013). In less developed countries the prevalence has been reported as 6.9% to 9.3% (Boivin 2007). It is presumed that the differences in the prevalence of subfertility in different populations in the industrialised countries are mainly due to differences in the definitions and methods of measurement used. Subfertility has been defined as failure to conceive after frequent unprotected sexual intercourse for one year in the absence of known causes of subfertility (NICE 2013).

Description of the intervention

Fertility drugs are used during the follicular phase of the menstrual cycle to increase the serum concentration of gonadotrophins, with the aim of promoting maturation of multiple follicles and consequently multiple ovulations. Commonly used ovulation induction agents include: 1) anti‐oestrogens, such as clomiphene citrate; 2) tamoxifen, a selective oestrogen receptor modulator (SERM); 3) human menopausal gonadotrophin (HMG), which contains follicle‐stimulating hormone (FSH) and luteinising hormone; 4) human chorionic gonadotrophin (HCG); 5) gonadotrophin‐releasing hormone agonists (GnRH‐AG); 6) gonadotrophin‐releasing hormone antagonist (GnRH‐A); 7) purified FSH; 8) growth hormone and 9) insulin‐like growth factor (IGF) (Duffy 2010). These hormones are used either alone or in combination depending on the cause of infertility and the protocol used. In addition, other fertility drugs used in most regimes of assisted reproductive technologies, such as in vitro fertilisation (IVF), include progestogens to support the luteal phase of the menstrual cycle (Genc 2011).

How the intervention might work

Clomiphene citrate and tamoxifen (a selective oestrogen receptor modulator) are used for women whose failure to ovulate is due to a hypothalamic pituitary dysfunction type II (World Health Organization Classification, WHO) (Rowe 1993). Both drugs are prescribed during the early phase of the menstrual cycle (day two to six) in order to reduce the negative feedback caused by oestrogen and to result in an increase in GnRH secretion from the hypothalamus, which in turn leads to a rise in FSH and luteinising hormone production. These natural gonadotrophin hormones then stimulate the ovary to mature a follicle and ovulate. Gonadotrophins (HMG or HCG or FSH) are used in the treatment of subfertility in women with proven hypopituitarism or who have not responded to clomiphene or in superovulation treatment for assisted contraception, such as IVF. They are given with the aim of amplifying and prolonging the endogenous secretion of FSH and to ensure that at least two or three follicles are developed, in order to maximise pregnancy potential.

Growth hormone, insulin‐like growth factor (IGF) and GnRH all increase the sensitivities of the ovaries to gonadotrophin stimulation and enhance follicular development (Poretsky 1999) and have been shown to have a role in fertility treatment, since they can improve the outcome of ovarian stimulation therapy. Co‐treatment with growth hormone combined with HMG and HCG for ovulation induction has been suggested as a way to improve follicle growth, and probably pregnancy rate, in patients with hypogonadotropic hypogonadism (Homburg 1995). This reduces the gonadotropin dose requirement, reduces the duration of HMG treatment and improves success rates (Duffy 2010). The IGF system is composed of two ligands (IGF 1 and 2), two receptors and insulin‐like growth factor binding proteins (IGFBP). Women treated for subfertility with IGF require a lower gonadotropin stimulation dose and induction time (Genc 2011).

Studies have suggested that one long‐term effect of fertility drugs could be the development of ovarian cancer or borderline ovarian tumours. Borderline ovarian tumours possess many of the same morphological features as their malignant counterparts, but they do not destructively invade the ovarian stroma, and the women in whom they develop have a significantly more favourable prognosis than those with invasive ovarian cancers. Since the aetiology is largely unknown, it is difficult to explain the possible association between invasive ovarian cancers and borderline tumours, reproductive risk factors and the use of fertility drugs. However, it has largely been established that risk factors for the disease relate mostly to reproductive events and there is also a general agreement on the protective effects of pregnancy (Rish 1994) and oral contraceptive use (Whittemore 1992a). Several hypotheses have postulated ovulation as a potential biologic promoter of ovarian cancer. Research has shown that epithelial ovarian cancer might be caused by repeated ovulations, which disrupt the ovarian epithelium and lead to malignant transformation of the epithelial cells, the so called 'incessant ovulation' hypothesis. Genetic alterations may develop, due to the many micro‐traumata and the high mitotic activity associated with ovulation, eventually causing autonomic growth of the malignant cells (Fathalla 1971). According to the 'incessant ovulation' theory, promoting ovulation by ovulation induction medications might increase the frequency of invasive ovarian tumours, whilst any factor which suppresses ovulation, such as pregnancy, oral contraception, lactation and an early menopause, might reduce the risk of cancer.

Fertility medication stimulates multiple oocytes so there is simultaneous maturation and ovulation during one cycle. This serves to increase the mechanical trauma and the number of epithelial inclusions in the surface epithelium of the ovary (Meirow 1996). It has been estimated that a single cycle of ovulation induction, preparing for IVF, can be equivalent to two years of normal menstrual cycles, in term of the number of follicles produced and oestrogen concentrations achieved (Attia 2006). However, some epidemiological studies contradict this link (Booth 1989; Brinton 1989; Ron 1987; Rossing 1994; Whittemore 1992a). The risk of ovarian cancer in these studies was increased in women with ovulatory disturbances (either lack of ovulation or reduction in the number of ovulations over one year), while according to the 'incessant ovulation' theory, these women would have been expected to have a reduced risk of ovarian cancer. Moreover, Balasch 1993 critically reviewed the literature concerning follicular stimulation and ovarian cancer and concluded that even if an association between ovulation induction and ovarian cancer was found, it would not necessarily indicate an effect of ovarian stimulation. A more likely explanation is that an underlying ovulatory disorder or the absence of pregnancy predisposes the woman to cancer of the ovary (Balasch 1993).

The second hypothesis proposes a model in which persistent stimulation of gonadotrophins increases the risk of malignant changes directly, or by acting in combination with a raised concentration of oestrogen (Rish 1998). The gonadotrophin theory is based on the animal studies of Biskind carried out in 1944 (Biskind 1944). In this study, it was found that rats developed ovarian tumours of stromal origin (no epithelial tumours occurred) when they were manipulated to produce high concentrations of gonadotrophins.

Nevertheless, these data do not prove the existence of a casual relationship between iatrogenic raised serum gonadotrophin concentrations (i.e. prescribed by a health care provider and not naturally produced by the body) and the development of granulosa cell tumours. Other explanations are possible, such as tumour presence before fertility treatment initiation, or that the onset of the tumour during fertility treatment was coincidental (Meirow 1996). A study has suggested that persistent stimulation of the ovary by gonadotrophins may have a direct effect or may act through, or in combination with, raised concentrations of oestrogen (Henderson 1998). The gonadotrophin model is consistent with the known protective effects of each additional pregnancy and duration of oral contraceptive use, since both pregnancy and oral contraceptive use have been shown to lower basal as well as peak gonadotrophin stimulation (Henderson 1998). Another hypothesis frequently suggested is that an undiagnosed early ovarian cancer causes, in some manner, subfertility. This hypothesis was based upon epidemiological data which showed an increased rate of subfertility in patients with ovarian cancer (Harris 1992; Whittemore 1992a).

Why it is important to do this review

In spite of the increase in women requesting fertility treatments, and the incidence of ovarian cancer in most Western countries, the question of whether ovarian stimulation increases the incidence of ovarian cancer as an independent factor is still unanswered. Additionally, it is still difficult to separate the possible role of fertility drugs from underlying subfertility as risk factors for ovarian cancer. Although these are seemingly straightforward questions, ovarian cancer is a relatively rare outcome, and mostly occurs late in life, many years after normal childbearing age or fertility therapy. Moreover, there is still uncertainty over the role of various drugs, since limited information is available on the different potential effects they may have. An evaluation of risk factors for ovarian cancer was published in a combined analysis of 12 US case‐control studies of ovarian cancer diagnosed between 1956 and 1986 and conducted by the Collaborative Ovarian Cancer Group (US) (Whittemore 1992b). Only three of the 12 studies examined the association between the use of fertility drugs and invasive ovarian cancer; the others evaluated different reproductive and menstrual risk factors. The study showed a 2.7‐fold increased risk of ovarian cancer in subfertile women who had used fertility drugs as compared to no use and a 27‐fold higher risk in subfertile women who had never been pregnant compared to subfertile women who had been treated and conceived. In this study, subfertile women who had not used fertility drugs experienced no increased risk of ovarian cancer compared with women without a history of subfertility (Whittemore 1992b). This study had limitations, for example few of the women had used fertility medications, making the confidence interval around the risk estimates wide, and some of the fertility drugs when used were outdated (such as conjugated oestrogen and diethylstilbestrol) (Mahdavi 2006). Moreover, there was poor information given about the reasons for subfertility in the women included which made it impossible to separate the treatment effects from ovulatory abnormalities that themselves may increase the risk of ovarian cancer. Moreover, little or no information on the types of medications used or the duration of treatment was provided and also patients with ovarian cancer may have been more likely than the controls to recall their exposure to fertility drugs (recall bias), which could have overestimated the risk of association. Subsequently, a large cohort study also suggested an increased risk of invasive and borderline ovarian tumours among women using clomiphene citrate for 12 months or more (Rossing 1994), and between the use of fertility medications and non‐epithelial cancers (Horn‐Ross 1992). This finding was also confirmed by other authors (Harris 1992; Ness 2002; Nugent 1998; Parazzini 1998; Shushan 1996)

In contrast, several other epidemiological studies failed to confirm the above findings and do not show any association between women exposed to treatment with ovulation‐inducing drugs and untreated infertile woman (Brinton 2004; Dor 2002; Doyle 2002; Franceschini 1994; Jensen 2009; Modan 1998; Mosgaard 1997; Mosgaard 1998; Rossing 2004; Venn 1999).

Several reviews have evaluated the long‐term effects of ovulation‐promoting drugs on cancer risk (Brinton 2005; Brinton 2012; Gadducci 2013; He 2012; Mahdavi 2006) and, to our knowledge, there are only three systematic reviews and meta‐analyses (Kashyap 2003; Li 2013; Siristatidis 2013) evaluating the literature regarding the relationship between fertility drugs and ovarian cancer. One included seven case‐control and three cohort studies (Kashyap 2004), one included only six cohort studies (Li 2013) and the last published included only nine cohort studies calculating the risk of ovarian cancer in infertile women treated with fertility drugs. The authors in two of these meta‐analyses (Kashyap 2003; Li 2013) reported a significant elevated risk of ovarian cancer in treated subfertile patients when compared to the general population. However, data from cohort studies that compared treated with untreated subfertile patients suggests that treated patients may tend to have a lower incidence of ovarian cancer (Kashyap 2004). The last published meta‐analysis reported that fertility treatment is not associated with an elevated risk of ovarian cancer (Siristatidis 2013). This meta‐analyses included only some of the observational studies published on this topic up to 2013. It is therefore important to conduct an updated systematic review including all the available evidence published up to 2013.