By Kate Madden Yee, staff writer

April 13, 2016 -- Infertility treatments, particularly what is called controlled ovarian stimulation (COS), may increase a woman's breast density -- and therefore her breast cancer risk, according to a new study published in Breast Cancer Research.

The findings could be bad news for the long-term health of women who struggle with infertility, study lead author and PhD candidate Frida Lundberg from the Karolinska Institute in Stockholm told via email.

Frida Lundberg
Frida Lundberg from the Karolinska Institute.

"Fertility treatments involve stimulation with potent hormonal drugs that increase the amount of the sex hormones estrogen and progesterone, and these hormones have been linked to breast cancer risk," she said. "Since these treatments are relatively new, most women who have gone through them are still below the age at which breast cancer is usually diagnosed, which is why we wanted to conduct this research."

The study is the first to investigate a possible link between infertility and breast density, according to Lundberg and colleagues.

"To our knowledge, this is the first study addressing the impact of infertility and different hormonal fertility treatments on mammographic density, including COS," they wrote.

Is there a connection?

Lundberg and colleagues used data from the Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA), a national digital mammography screening-based study conducted between 2010 and 2013. Lundberg's group included 43,313 women between the ages of 40 and 69 in the study. All of the women completed a questionnaire that elicited information about their age; education; reproductive health, including infertility status and/or fertility treatments; medication, including hormone replacement therapy; lifestyle factors; any comorbidities; and family history of breast cancer (Breast Cancer Res, April 13, 2016).

Infertile women from the study cohort were further categorized into three groups: those who had controlled ovarian stimulation for in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), those who had other hormonal treatment to induce ovulation (clomiphene citrate or low-dose gonadotropins, but no COS), and those who did not have hormonal treatment.

The women's mammographic density was measured from full-field digital mammograms acquired at their entry into the study and with the VolparaDensity software from Volpara Solutions.

Of the 43,313 women, 20.7%, or 8,963, reported fertility problems. Of these, 1,576 had undergone controlled ovarian stimulation, 1,429 had received hormonal treatment without COS, and 5,958 did not undergo any hormonal treatment.

The researchers found that women with a history of infertility did have higher breast density volumes than women without infertility, with the highest difference for women who underwent COS.

Breast density according to fertility treatment
  No infertility (n = 34,360) History of infertility
No hormonal treatment (n = 5,948) Hormonal treatment only (n = 1,429) COS for IVF/ICSI (n = 1,576)
Absolute dense volume, cm3 62.8 64 64.8 73.8
Absolute nondense volume, cm3 773 805 804 706
Percent dense volume 9.2% 9% 9.3% 11.4%

Overall, once the data were adjusted for age, women with a history of infertility had a 3.12 cm3 higher absolute dense volume than women without infertility; their absolute nondense volume was 13.8 cm3 higher. Overall percent dense volume was marginally higher for women with a history of infertility compared to those without, but it did not reach statistical significance.

"Both absolute and percent dense volumes are associated with breast cancer risk," Lundberg and colleagues wrote. "The fibroglandular tissue in the breast, represented by the absolute dense volume, is considered the target tissue for tumor development."

More work to be done

The results suggest that infertile women, especially those who undergo COS, might represent a group with an increased risk of breast cancer. But more studies need to be done to firmly establish a link between hormonal treatments for infertility and increased cancer risk, Lundberg said.

"It is still unclear whether the difference in density is due to COS or the underlying infertility," she told "We need to see these results repeated in further studies before worrying the women who are going through these stressful treatments."

Copyright © 2016

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