A group of Danish researchers have reported that drugs commonly administered to treat infertility, such as gonadotropins, clomiphene citrate and human chorionic gonadotropin (hCG), may increase the long term risk of uterine cancer; with greater risk associated with higher doses and longer use. The findings of the study have been published in the recent issue of the American Journal of Epidemiology.
Allan Jensen and co-workers from the Institute of Cancer Epidemiology, Danish Cancer Society, Denmark, conducted the case-cohort study in 54,362 infertile women referred to Danish fertility clinics from 1965 to 1998. The study determined the impact of 4 fertility drug groups on uterine cancer risk using rate ratios (RR) and 95% confidence intervals (CI), after adjusting for probable confounding factors.
A total of 83 uterine cancers were identified through mid 2006. The following findings were observed during the study:
• Ever use of any of the fertility drugs was not linked to the risk of uterine cancer (RR=1.10; 95% CI=0.69, 1.76), but ever use of human menopausal gonadotropin and follicle-stimulating hormone was found to be associated with increased uterine cancer risk (RR = 2.21; 95% CI=1.08, 4.50), which was noted following a 10-year follow-up period.
• The risk for uterine cancer increased with the number of cycles for clomiphene (≥6 cycles; RR=1.96; 95% CI=1.03, 3.72) and hCG (≥6 cycles; RR=2.18; 95% CI=1.16, 4.08) use.
The risk of developing the cancer was, however, not associated with other gonadotropins and gonadotropin-releasing hormone analogs. Based on the findings, the researchers suggested that gonadotrophins, clomiphene and hCG administration was associated with an increased risk of uterine cancer, especially with higher doses and longer follow-up.
Earlier, a retrospective cohort study by Althuis et al (American Journal of Epidemiology, 2005) also reported elevated uterine cancer risk with the use of clomiphene citrate. The study investigated 8,431 US women, who were evaluated for infertility between 1965 and 1988. The researchers noted that the risk for cancer increased with the dose (>900 mg), number of menstrual cycles of its use (≥6 cycles), and the time since its initial use (≥20 years). Clomiphene users who were nulligravid or obese were at a higher risk, and the risk was further elevated in women who were both nulligravid and obese.
Contrary to these findings, a case-control study conducted by Parazzini et al (Human Reproduction, 2001) in Italy, documented no association between endometrial cancer risk and the use of fertility drugs.
With an increasing number of women being administered fertility drugs, it is crucial to draw a balance between the adverse effects and benefits, especially in assisted conception. It is also important to educate the patients on the possible association of the fertility drugs with the risk for cancer while obtaining their informed consent for initiation of the treatment.
References
1. Jensen A, Sharif H, Kjaer SK. Use of fertility drugs and risk of uterine cancer: results from a large Danish population-based cohort study. Am J Epidemiol. 2009 Dec 1;170(11):1408-14.
2. Althuis MD, Moghissi KS, Westhoff CL, et al. Uterine cancer after use of clomiphene citrate to induce ovulation. Am J Epidemiol. 2005 Apr 1;161(7):607-15.
3. Parazzini F, Ricci E, Rosa C, Negri E, La Vecchia C. Risk of endometrial cancer after use of fertility drugs. Hum Reprod. 2001 Jan;16(1):196.
