The ASRM published their 2024 guidelines on cancer and fertility drugs, offering an overview of the latest research on whether fertility drugs raise the risk of cancer.
Concerns over fertility drugs and cancer are due to the ability of fertility drugs to modify hormone levels. Estrogen can promote tumor development because it can stimulate cell proliferation and decrease apoptosis, particularly in tissues where there’s a lot of estrogen receptors, such as the female reproductive tract, breast and colon (Liang et al. 2013).
The ASRM recently published their 2024 guidance on fertility drugs and cancer, reviewing 52 different studies published since 2015. These studies were reviewed by dozens of ASRM members and summarized in their guide, giving recommendations to improve patient care. You can read their full guidance here, which contains all the details and references.
They rated the strength of evidence as high, moderate and weak. High-quality evidence comes from well-designed studies like randomized controlled trials with large sample sizes and minimal bias. Moderate quality evidence may benefit from further research to refine its findings. Weak evidence often has significant methodological flaws and small sample sizes, leading to uncertain conclusions.
🔗 Original studies are referenced in this post or within the linked Remembryo posts.
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Ovarian cancer and IVF drugs
Studies have shown varying results with ovarian cancer and fertility drugs:
- Some studies indicate no increased risk or an increased risk of ovarian cancer (Luke et al. 2015, Vassard et al. 2019)
- Some studies suggest that some of the risk of ovarian cancer is due to the underlying infertility diagnosis itself (Lundberg et al. 2019). Kvaskoff et al. 2021 found an increased risk of ovarian cancer in endometriosis patients.
- A 2019 Cochrane review found that the risk of ovarian cancer increased slightly in women with infertility treated with fertility drugs compared to untreated women or the general population. This risk was mostly in women who never had a birth (nulliparous) compared to women who did (multiparous).
Overall, the ASRM states that the evidence shows that fertility treatments are associated with ovarian cancer. The risk is likely very small (3 more cases per 100,000 person-years) and may be related to underlying diagnoses or parity. For a subtype of ovarian cancer, known as borderline ovarian tumors, the ASRM states that there may be an increased risk based on available evidence, which may be due to the underlying infertility diagnosis itself. The strength of evidence was rated as moderate (and weak/moderate for borderline ovarian tumors).
Breast cancer risk and fertility drugs
Breast cancer is the most common cancer among women and is influenced by hormonal factors, with estrogen and progesterone playing an important role. A common belief is that higher estrogen and progesterone levels during ART might be linked to breast cancer, although these exposures are short-term and might only be an issue with multiple cycles.
The ASRM notes that most studies indicate no significant increase or even a decreased risk of breast cancer following infertility treatments compared to untreated women or the general population.
- A study by Reigstad et al. (2015) found a slightly higher risk of breast cancer, but the follow-up time was short.
- Meta-analyses by Gennari et al. (2015), Russo et al. (2015), Zriek et al. (2010), and others have found no association. A more recent meta-analysis by Cullinane et al. (2022) found no increased risk of breast cancer, even in women who had six of more IVF cycles (not listed in the ASRM guidance).
- Kvaskoff et al. 2021 found a slight increased risk of breast cancer in endometriosis patients (not listed in the ASRM guidance).
Although most studies show no link between fertility treatments and breast cancer, some report increased risks associated with clomid use (Gennari et al. 2015).
Overall, the ASRM states that there isn’t any increased risk of breast cancer with ART treatment, although prolonged use of clomid should be avoided. The strength of evidence was rated as moderate.
Uterine cancer and fertility medications
Type 1 endometrial cancer is associated with estrogen and progesterone can be protective, suggesting that fertility drugs might increase or decrease the risk of this cancer.
The evidence shows mixed results:
- Some studies indicate an increased risk of endometrial cancer in women with PCOS or obesity, especially those using clomid (Klip et al. 2000, Althuis et al. 2005).
- One study by Murrugappan et al. (2019) found that PCOS/endometriosis may be linked to uterine cancer.
- A 2017 Cochrane review found no increased risk of endometrial cancer in women taking fertility drugs, based on low quality evidence. They did find that patients taking high doses of clomid (>2000 mg) and having a high number of cycles (>7) were associated with increased risk, but it might be associated more with their underlying diagnosis (ie. PCOS) than the drug itself.
Overall, the ASRM indicates that there is no definitive evidence linking an increased risk of uterine cancer with the use of fertility drugs. However, they acknowledge that underlying infertility conditions such as PCOS are associated with higher uterine cancer risks. The strength of evidence was rated as moderate.
Thyroid cancer and IVF medications
Thyroid cancer is about 3 times more common in women than men, and research on the link between fertility drugs and thyroid cancer has shown varied results:
- Some studies didn’t find a significant increase in thyroid cancer risk (Brinton et al. 2015), while one study did find an association, particularly in patients taking clomid (Hannibal et al. 2008). A 2018 meta-analysis found an increased with thyroid cancer in women taking fertility drugs, especially clomid.
- Women with an infertility diagnosis have been shown to have a higher risk of thyroid cancer (Murrugappan et al. 2019). Kvaskoff et al. 2021 found an increased risk of thyroid cancer in endometriosis patients (not listed in the ASRM guidance).
Overall, the ASRM states that there may be an increased risk of thyroid cancer and fertility treatment, particularly among those with high exposure to clomid. The strength of evidence was rated as weak.
Cervical cancer and IVF drugs
Studies for cervical cancer risk in women taking fertility drugs have shown either no association (Kessous et al. 2015, Pup et al. 2018) or have shown a decreased risk (Kristiansson et al. 2006, Yli-Kuha et al. 2012).
Overall, the ASRM states that fertility drugs aren’t associated with an increased risk of cervical cancer. The strength of evidence was rated as weak/moderate.
Other cancers
The ASRM also examined evidence for several other cancers:
- For colon cancer, the ASRM states that there’s no association with fertility medications. The strength of evidence was rated as weak/moderate.
- For non-hodgkin lymphoma, the ASRM states that there’s no enough evidence to determine if there’s a risk with fertility drugs. The strength of evidence was rated as weak.
- For malignant melanoma, the ASRM states that there’s no enough evidence to determine if there’s a risk with fertility drugs. The strength of evidence was rated as weak.
Conclusions
In their 2024 guidance, the ASRM found:
- For ovarian cancer, there may be an increased risk, though it’s likely very small and might be due to certain diagnoses (like endometriosis).
- For breast and uterine cancer, there doesn’t seem to be any increased risk, although there may be with prolonged clomid (clomiphene) use.
- For thyroid cancer, there may be an increased risk, particularly for those exposed to high amounts of clomid.
- For cervical and colon cancer, ASRM didn’t find any associations with fertility drugs. For non-hodgkin lymphoma and malignant melanoma, there wasn’t enough evidence.
The ASRM noted problems with studying the link between cancer and IVF drugs:
- In retrospective studies, participants may not accurately remember past exposures to fertility drugs.
- Patients may have underlying conditions like endometriosis, nulliparity, or anovulation, which independently increase cancer risk. Parity can reduce a woman’s exposure to estrogen and progesterone by decreasing the number of menstrual cycles in a lifetime, which lowers the risk of breast, ovarian, and endometrial cancers. Additionally, pregnancy-induced changes in breast cells make them less likely to develop into cancer cells (National Cancer Institute).
- Many studies do not follow participants long enough to observe long-term effects, as cancers often develop years later.
- Studies often report inconsistent findings, making it difficult to draw definitive conclusions about the relationship between fertility treatments and cancer risks.
- Some studies may not distinguish between clomid and gonadotropins.
- Older studies may have not used gonadotropins (they weren’t available until the late 1980’s), and instead may have used clomid.
Reference
About Embryoman
Embryoman (Sean Lauber) is a former embryologist and the founder of Remembryo, an IVF research and fertility education website. After working in an IVF lab in the US, he returned to Canada and now focuses on making fertility research more accessible. He holds a Master’s in Immunology and launched Remembryo in 2018 to help patients and professionals make sense of IVF research. Sean shares weekly study updates on Facebook, Instagram, and Reddit regularly. He also answers questions on Reddit or in his private Facebook group.
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