While many highly industrialized and developed countries report falling or negative population growth rates due to a rapid decrease in the number of babies born each year, a new report adds more strength to the evidence that bearing a baby has a protective effect on the endometrium, the lining of the womb, reducing the risk of endometrial cancer. These findings were reported in the journal BMC Medicine by researchers at the University of Bristol, the University of Oslo, and the University of Queensland.

Study: Mendelian randomization analysis of factors related to ovulation and reproductive function and endometrial cancer risk. Image Credit: crystal light / Shutterstock

Introduction

Endometrial cancer (EC) is a deadly disease, ranking sixth worldwide among female cancers. It takes hundreds of thousands of lives every year, with new cases increasing globally, especially in developing countries.

Earlier epidemiological observations have shown that many factors are related to this condition, including ovulation and pregnancy. This is possibly due to the exposure to estrogen involved with these states. In fact, oral estrogen increases the risk of EC, as has been observed with estrogen-only hormone replacement therapy (HRT) for menopausal symptoms.

The risk is reduced when progesterone is added to the HRT, hinting that the ratio of estrogen to progesterone is the culprit in EC development. The combined oral contraceptive pill (COCP) that contains synthetic progesterone and estrogen has a protective effect against EC, which increases with the duration of use. Progesterone may be protective against EC, a theory supported by the reduced incidence of such tumors in women on long-term birth control with intrauterine progestin-secreting devices that suppress ovulation.

Interestingly, pregnancy, even when it ends in a miscarriage or induced abortion, is protective against EC to a greater extent than COCP use. EC risk is also reduced in women who had a live birth later in life. Explanations for these phenomena abound, including the shedding of abnormal cells with childbirth or abortion and the high levels of protective progesterone during pregnancy.

Both factors are likely to be even more important in older women who are typically at higher risk for malignancy of the endometrium, but in whom a late pregnancy leads to the removal of such cells before they can proliferate, either mechanically or because of the high progesterone levels of pregnancy.

An excessively high BMI remains the strongest predictor of EC risk, underlying EC in 40% of the cases in developed countries. This could also be due to higher estrogen exposure from the androgen-estrogen conversion facilitated by increased adipose tissue accumulation.

The relationship between BMI and EC could be due to associated increases in fasting insulin levels, the amount of testosterone available to the body, and the levels of sex hormone-binding globulin. The rising BMI globally could explain why cases are increasing in developing countries.

However, the question remains whether these are causes of endometrial cancer and if so, whether they act independently or have additive or synergistic effects.

Specifically, this study aimed to examine how ovulatory years and the number of babies born to a woman correlate with endometrial cancer risk and, if a relationship were found, to determine whether it could be causal.

The observational study used data from the UK Biobank (UKBB), which contains over 270,000 women. Only white European women were included in the current study.

Multiple variables were included, and confounding factors were accounted for as far as possible. The researchers also used the Mendelian randomization (MR) technique to evaluate the potential for causality. Here, genetic variants decide the causality of an association between an exposure and an outcome.

To do this, they collected the number of live births per woman from earlier studies and her age at first period and menopause. The body mass index (BMI) was also factored in, as was the age at the time of the last live birth. These data were then analyzed by genome-wide association analysis to detect single nucleotide polymorphisms (SNPs) that occurred genome-wide. They were associated with a higher number of years ovulating, years on contraceptive pills, or with age at the last birth.

What did the study show?

The study's results, which involved hundreds of genetic variants, showed six to be strongly linked to more live births and reduced EC risk. The findings showed that the risk of endometrial cancer was inversely proportional to the number of live births. Women who had given birth to three babies had half the risk of EC compared to those who hadn't given birth. Similarly, the risk was increased in women who ovulated for a larger number of years.

"Researchers found evidence that suggested reducing years ovulating could reduce the risk of endometrial cancer, but the strongest links pointed to childbirth."

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EC risk is known to be associated with a lower age at menarche, higher age at menopause, and a higher BMI. While individual factors seemed to show a strong positive or negative association with EC risk, this effect waned after adjusting for confounding factors, showing that the risk was related to the age at last live birth, menopause, and BMI.

With the MR analysis, after compensating for confounding factors, the risk of EC was reduced by more than a fifth for women who had delivered more babies. The risk reduction due to this factor was not affected by the other known risk factors.

The protective effect of childbirth could be due to the tumorigenic effect of unopposed estrogen, which is opposed by progesterone. This hormone rises rapidly in early pregnancy and remains high throughout gestation. This could explain the protective effect seen with COCP use, though this was not seen with the MR arm, perhaps because of missing genetic data or because it does not act via genetic mechanisms.

The association of EC with older age at menopause could be due to factors like a high BMI or older age at menarche and could be explained by the effect of these. However, MR failed to show an independent association between BMI and EC once other factors were adjusted.

"Our findings highlight the importance of accounting for other predetermined risk factors with strong effects when conducting MR analyses."

Conversely, the negative association of the number of live births with EC risk on MR analysis could not be explained by the impact of age at menarche or natural menopause or the BMI. However, these could have affected the relationship.

The study also turned up several loci associated with age at last birth and years ovulating on GWAS, but many of these could be due to the effect of higher education with the associated delay in beginning a reproductive career or to the age at menopause.

Conclusion

A higher number of pregnancies was found to be an important protective factor, irrespective of the pregnancy outcome. This corroborates earlier studies. When separately examined, stillbirths appeared to be non-protective, unlike live births, but the researchers recommend further analysis before this is accepted as valid.

Similarly, incomplete pregnancies, whether spontaneous or induced abortions, were related to a reduced risk of EC but less so than a full-term pregnancy. Interestingly, a history of more induced abortions also carried a more significant protective effect on EC risk than live births. This could be due to the rapid rise in progesterone compared to estrogen early in pregnancy.

This does not explain why induced abortions are more protective than either miscarriages or live births, which share the same level of risk reduction. Perhaps women who tend to have terminations differ in some way from those who do not, or the process of abortion includes some specific protective factors.

Many questions remain due to the lack of data, such as whether women who had a lower age at natural menopause and should therefore have had a lower risk of EC did not experience such protection because they were on estrogen-only HRT. The researchers did not know the age at EC diagnosis, though this is a significant risk factor.

There is a lack of consistency between the conclusions of the multivariate and MR arms of the analysis, probably because much of the latter was limited by the lack of genetic variant data. The MR analysis failed to confirm the strong positive and negative associations of ovulating years and COCP use on EC risk.

"To our knowledge, this is the first study to report that number of live births may have a protective effect on the risk of EC, even when accounting for other risk factors."

Further research is necessary to disentangle the effect of late age of last live birth on the EC risk from that of having more live births. Moreover, the disagreement between the two analyses requires to be resolved.  

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.