Fertility drug use may have unwanted consequence

Exposure to fertility drugs appears to confer a modest risk of developing malignant melanoma, as shown in a study.

“To the best of our knowledge, this study is the largest to date to assess the association between use of fertility drugs and malignant melanoma. We observed that infertile women who had ever used fertility drugs had a 14-percent [risk increase] compared with fertile women,” according to researchers from the Danish Cancer Society Research Center, Copenhagen, Denmark.

“Furthermore, ever use of specific types of fertility drugs (clomiphene, gonadotropins, human chorionic gonadotropin [hCG], gonadotropin-releasing hormone [GnRH]-analogues, or progesterone) were all associated with an increased risk of malignant melanoma of about the same magnitude, indicating no differential effect of the different fertility drug types,” they added.

The study used data from a large nationwide cohort of women aged 20–45 years and residing in Denmark. There were 1,330,954 women in total, of whom 86,231 (6.5 percent) were treated with fertility drugs.

Over a median follow-up of 21.0 years, 6,139 women were diagnosed with malignant melanoma. Cox proportional hazard regression models showed that the hazard ratio associated with use of any fertility drugs was 1.14 (95 percent confidence interval [CI], 1.02–1.27). [J Invest Dermatol 2021;doi:10.1016/j.jid.2021.02.752]

The estimates associated with specific types of fertility drugs ranged from 1.09–1.13 but did not reach statistical significance. When it came to histological types, use of fertility drugs was linked to an increased risk of superficial spreading malignant melanoma and nodular malignant melanoma.

“Finally, the findings did not change substantially when infertile women not treated with fertility drugs were used as the reference group, suggesting that the observed increased risks are caused by use fertility drugs and not entirely by factors (ie, biological and/or genetic) related to the underlying fertility problems, which also support that the findings are not due to confounding by indication,” the researchers pointed out.

While postulating that fertility drugs trigger melanoma carcinogenesis, the researchers acknowledged that such a process is usually long and can take several years. The median follow-up time of 7.2 years between age at first use of any fertility drugs and age at malignant melanoma diagnosis may be too short to initiate a new melanoma, they said.

“[I]t is likely, at least for some of the observed malignant melanomas in the present study, that the increased oestrogen and progesterone levels associated with fertility drugs may accelerate the growth of an already existing preclinical melanoma in situ to become clinically detectable as a malignant melanoma within the follow-up time,” the researchers explained.

They shared that they would continue to monitor the risk in their study cohort, given that many of the women have not yet reached the normal peak age for malignant melanoma.

“We will continue and also encourage additional large, long-term follow-up studies with appropriate confounder control in order to try to establish a more definitive link between use of fertility drugs and malignant melanoma,” the researchers said.