History of infertility associated with risk of developing obesity-related reproductive cancers

The Nurses’ Health Study has found an association between a history of infertility and obesity-related cancers, including postmenopausal breast cancer.

Published 05 April 2023

A further analysis from the ongoing Nurses’ Health Study, which last year suggested a link between irregular menstrual cycles and (obesity-related) endometrial and colorectal cancers, now extends the association to infertility itself.

Women with a history of infertility may need more screening for obesity-related gynaecological cancers, according to the latest report from the long-running Nurses’ Health Study.(1) The study, now in its third cohort since its establishment in 1976, found that fertility patients have 17% higher odds of developing these malignancies long-term, especially those who experience infertility early on in their reproductive life

Based on data from more than 103,000 women and nearly 7000 invasive cancer cases, the findings, say the authors, help fill evidence gaps on the link between cancer and infertility. It is already documented that the risk of gynaecological cancers is increased by factors associated with the inability to conceive; lower parity and more lifetime ovulatory cycles, for example, have been linked with ovarian cancer. Yet studies into the association between infertility and other cancers, including obesity-related, have proved inconclusive.
In 2022 the same Nurses’ Health Study reported that irregular and long menstrual cycles throughout the reproductive lifespan were associated with an increased risk of total invasive cancer, especially obesity-related cancers.(2,3) Now, the authors of this latest analysis test a similar hypothesis that a history of infertility may also increase cancer risk, and again especially for obesity-related malignancies.

Data were included from the Nurses’ Health Study II (running from 1989 to 2015) on 103,080 women aged 25-42 years who were cancer-free at the outset, had either been pregnant/infertile or became pregnant/infertile during the study. At enrolment, participants reported their pregnancies and/or infertility history, including causes. Infertility was defined as failure to conceive after one year of trying.

Follow-up questionnaires every two years asked the women about subsequent pregnancies/infertility, and about cancer diagnoses. Other details such as height, weight, oral contraceptive use and family history of cancer were also recorded. Follow-up was calculated from the date women returned the questionnaire (with the first report of a pregnancy/infertility) until the date of cancer diagnosis, death, or the end of follow-up in 2015.

A total of 26,208 nurses reported infertility during follow-up, with ovulatory disorders (29%) the most common underlying cause; 6925 invasive cancer cases reported. These were classed as obesity-related (colorectal, gallbladder, kidney, multiple myeloma, thyroid, pancreatic, esophageal, gastric, liver, endometrial, ovarian and post-menopausal breast) or non-obesity related (all other cancers).

Results showed that women reporting infertility had 7% higher odds (HR 1.07) of developing cancer in general than those without infertility, after adjusting for BMI and other risk factors. The association with infertility was stronger with obesity-related cancers (HR 1.13 vs non-obesity-related cancers), restricted to obesity-related cancers. After adjusting for risk factors, the overall risk of developing gynaecological cancers (2009 cases) was 17% higher for women with a history of infertility than for those without. The younger a woman was when infertility first occurred, the greater her risk of obesity-related cancer. Incidence ranged from 19% higher for those with a first experience before 25 years old to 7% for those aged above 30 years.

The findings failed to support the authors’ initial hypothesis that common abnormal characteristics in infertile women would increase the obesity-related cancer risk. No link was observed, they say, between infertility and obesity-related but non-gynaecologic cancers (eg, thyroid). Instead, they suggest that other infertility-related factors, such as delayed age at first birth, may be responsible for a ‘small elevation’ in the risk of reproductive cancers.

In an attempt to explain the association between early onset of infertility and cancer risk, the authors say the likelihood that this infertility is primary (not secondary) makes it ‘biologically plausible’. Conversely, they suggest leanness (a BMI under 18) in earlier life may ‘mitigate the hormonal disturbances and immune aberrations’ which link infertility with obesity-related cancer.

In terms of the message for practitioners, the authors conclude that they should consider informing patients with an infertility history about their long-term health risks, maintain regular follow-up and encourage lifestyle changes.

1. Wang S, Gaskins AJ, Farland LV, et al. A prospective cohort study of infertility and cancer incidence; Fertil Steril 2023;
2. Wang S, Wang YX, Sandoval-Insausti H, et al. Menstrual cycle characteristics and incident cancer: a prospective cohort study. Hum Reprod 2022; 37: 341-351;

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