All over the world, many couples cannot conceive a child naturally, facing complex infertility problems, both female and male. Infertility is defined as the failure to conceive a child despite frequently unprotected sexual intercourse for a year in the absence of a known etiology. The incidence of infertility varies around the world between 3% and 33%, so that in developed countries we have an average reporting of 3.5-16.7%, while in less developed countries there is a prevalence of 6.9-9.3%. Approximately 19% of the Romanian population faces this medical problem of national interest because we want to increase the birth rate, and 1 in 5 couples has infertility issues, similar to what happens in other European countries. Studies have shown that 1 in 10 couples resorts to stimulation treatments. Current evidence shows that 56% of infertile couples need medical advice and infertility treatment attention(1).
In 2018, the first study of the Romanian Human Reproduction Association showed that, in Romania, similar to countries worldwide, the reproductive behaviour had undergone important changes. In Romania, the fertility rate is at a declining level as well. Of the 4680 respondents, couples who have been trying to have a child for more than one year, 81% are married (25% from Bucharest/Ilfov), 74% have university and postgraduate studies, 47% have an income over 50,000 RON, and 76% have their own house(2).
There are concerns about the long-term risk of infertility drugs that could be involved in cancer occurrence. This may be due to multiple modes of action, all of which can induce multiple ovulation and alter steroidogenesis. The relationship between fertility drugs for ovarian stimulation and cancers (ovarian, endometrial, colon, thyroid or skin) remains controversial(3).
This paper is a narrative review of the recent literature on the association between fertility medication and gynecological cancer risk. Our objective was to discuss the medium- and long-term effects of hormonal stimulation in infertile patients who are diagnosed with malignancy years after.
There is controversial information in the literature, some studies indicating an increased risk of epithelial ovarian cancer due to ovarian stimulation. Other studies state that there is no link between stimulation and ovarian cancer, focusing more on other reproductive factors influencing ovarian cancer risk(4). On the other hand, some studies show that clomiphene citrate increases cancer risk, and others state that drugs reduce the risk of ovarian cancer(3).
The following types of cancer related to hormonal stimulation were reported: ovarian cancer, breast cancer, endometrial cancer, melanoma, non-Hodgkin lymphoma, cervical cancer, thyroid cancer, colon cancer, persistent trophoblastic tumors.
Hormones can act as powerful carcinogens due to their ability to initiate and promote the development of cancers. Excessive hormonal stimulation of cell proliferation increases the risk of mutation and the subsequent proliferation of mutant cell clones(5). As already known, some types of cancer, including breast and gynecological cancers, are hormone-dependent, realizing the physiological mechanism between the use of drugs to increase fertility and cancer risk.
Fertility drugs are used during the follicular phase of the menstrual cycle to increase the serum concentration of gonadotropins in order to produce follicle maturation and development.
Many factors are involved in the epidemiology of ovarian cancer: heredity, reproductive history, hormonal, inflammatory, dietary, surgical, and geographic factors that may influence ovarian cancer risk(7).
High doses of ovarian stimulation medication can lead to hormonal stimulation, and multiple stimulations can increase the risk of ovarian hyperstimulation syndrome.
Letrozole and clomiphene citrate in monotherapy or in combination with metformin are currently the preferred drugs for anovulatory patients. They seem to be associated with a long-term risk of borderline ovarian tumors and sometimes even with ovarian cancer(8).
Hypotheses supporting the link between the use of fertility drugs and cancer
One explanation for the pathogenesis of ovarian cancer caused by fertility drugs, ovulation and overstimulation is the fact that the ovary disrupts the ovarian epithelium and contributes to the malignant transformation of ovarian epithelial cells(6).
Ovarian microtrauma is associated with high mitotic activity and ovulation, leading to the growth of neoplastic cells. It has been estimated that a single cycle of ovulation induction in preparation for in vitro fertilization (IVF) may be equivalent to two years of normal menstrual cycles in terms of the number of follicles produced and the amounts of estrogen reached(9).
Another hypothesis suggests that undiagnosed early ovarian neoplasm may cause infertility(10).
Ovarian cancer and previous treatment for infertility
A Cochrane review found a 2.7-fold increased risk of ovarian cancer in infertile women who are using fertility drugs stimulation compared to those who had not used it, and a 27-fold higher risk in nulliparous women when compared to infertile women who received treatment and conceived(8).
The increased risk of ovarian cancer has been reported in women who have taken clomiphene citrate for more than 12 months. This meta-analysis concluded that there was no “definitive relationship between the use of fertility drugs and cancer”. Moreover, it was stipulated that estrogens protect against colorectal cancer, and the risk of cancer should decrease in women using fertility drugs. The carriers of the BRCA mutation may have a low ovarian reserve compared to women without the BRCA mutation and previous natural menopause.
The Guidelines of the Society of Reproductive Medicine in the United States of America consider that there may be a risk of cancer due to hormonal stimulation procedures, but at the same time claim that there are insufficient studies to prove this hypothesis. However, women should be informed of a potential risk of invasive ovarian, endometrial or breast cancer. The company’s review of 25,000 women found that the risk of invasive ovarian cancer did not increase after IVF compared to the general population (reported incidence of 0.86-1.88%), but the risk increased when the follow-up was less than 15 years (reported incidence of 1.62-6.72%)(11).
Most borderline ovarian tumors were diagnosed between 7 and 9 years after the administration of stimulation treatment(12).
Ovarian cancer accounts for 3% of all annual diagnoses of cancer in women. It is most often diagnosed in advanced stages due to inefficient and insufficient screening procedures.
A meta-analysis of 37 studies of women treated for infertility with ovarian stimulation has found a higher incidence of borderline ovarian tumors in infertile nulliparous patients compared to multiparous. Parity is considered a risk factor for cancer when dealing with infertility treatment.
There are cohort studies that demonstrated a significant association between borderline ovarian tumors and women receiving fertility treatment versus those not receiving treatment (SIR: 3.3; 95% CI; 1.1-7.8), based on five cases of borderline ovarian cancer(12-14). In a population of 19,861 women undergoing IVF matched with 6,604 subfertile women with an average follow-up of 14.7 years, the authors have found an increased risk of borderline ovarian tumors in the former women, adjusting for age, parity and fertility diagnosis (SIR: 1.79; 95% CI; 1.16-2.56). Unlike its invasive counterpart, borderline ovarian cancer has not been associated with parity, endometriosis or prior surgery(3). There are few studies, and the information on the dose or type of medication used is insufficient. An increased risk of ovarian cancer has been reported after clomiphene citrate administration for more than 12 months, with a standard incidence of 2.5%. The risk was increased by 3.95% after human menopausal gonadotropin and by 1.97 for combined menopausal gonadotropin and clomiphene citrate(4).
A report of evidence of ovarian carcinoma in 255,786 women after IVF followed for 8 years found that women who did not give birth to live children until the end of treatment had the highest risk of ovarian cancer due to high doses of drugs at each and repeated stage of in vitro fertilization(15).
One in three cycles of in vitro fertilization were correlated with a slight increase in the risk of ovarian cancer, but this has not been clinically significant. There was no increased risk of invasive ovarian cancer after using infertility drugs in women with BRCA mutations(16).
Breast cancer and previous treatment for infertility
Breast cancer is the most common malignancy in women worldwide, affecting 1 in 8 women. Breast cancer is correlated with female age. An increasing number of breast cancers diagnosed during pregnancy and the postpartum period is reported, mostly triple-negative invasive carcinoma(17,18). The exposure to exogenous steroids increased the estrogen levels and the circulating superphysiological sex steroids which theoretically may lead to an increased risk for breast cancer. A study from 2019 revealed an association between infertility treatment and breast cancer, but the risk was low(19). However, women may be at an increased risk for breast cancer if the infertility treatment was initiated at an early age or the woman had undergone several cycles of clomiphene citrate(20).
A recent review, including more than 10,000 women, revealed an increased risk of breast cancer in women who gave birth following assisted reproductive techniques (1.01-1.42%)(19). But the study did not consider risk factors for breast cancer such as the age of onset of menarche and pregnancy, family history, breastfeeding or obesity.
Luke et al., in a large prospective study of 113,226 women, found no association between assisted reproductive techniques (ART) and cancer risk. Women with other risk factors for cancer were at an increased risk for all cancers (HR 1.35; 95% CI; 1.04-1.75) and for breast cancer (HR 1.60; 95% CI; 1.07-2.39). The authors demonstrate no other increased risks by parity, assisted reproductive technology outcome, number of diagnoses or of ART cycles, or cumulative FSH dosage(21).
Endometrial cancer and previous treatment for infertility
Contradictory results regarding the effects of fertility drugs on endometrial cancer risk have been published, although several studies have calculated a possible increase in risk. It is well known that clomiphene citrate has similar chemical properties to tamoxifen, being linked to malignant endometrial transformation(22). Studies and systematic reviews reported equivocally an increased risk of uterine cancer associated with IVF medication, but not with clomiphene citrate used for the induction of ovulation(23-25). None of the studies did observe substantial variations according to BMI, a major endometrial risk factor for cancer, which has been shown to modify the effects of fertility drugs(23).
Gonadotropins are associated with higher increases in estradiol levels than clomiphene. These patients should continue to be monitored, including the other risk factors for endometrial cancer.
Most cases of endometrial cancer were reported in case of spontaneous abortion after ART, compared with successful live births.
Due to the unknown risks after IVF and ovarian stimulation, it is imperative to monitor these patients on the long term. Information on the types of drugs used, the dose and treatment duration could be prospectively recorded and correlated in national registries. Also, these registries may include types of treatments, such as monotherapy/multiple therapies, low-dose/high-dose treatment, the introduction of confounders, parity, the use of oral contraceptives, family history, types of infertility, doses, duration of treatment and the outcome of treatment.
Before infertility treatments, women should be evaluated for risk factors for cancers, including genetic risk factors, in order to assess the individual risk. Future prospective trials evaluating the relationship between cancer and infertility drugs at different ages are needed.