Abstract and Introduction
Abstract
Study Question: Are menstrual cycle characteristics throughout the reproductive lifespan associated with cancer risk?
Summary Answer: Irregular and long menstrual cycles throughout the reproductive lifespan were associated with increased risk of total invasive cancer, especially obesity-related cancers.
What is Known Already: Long and irregular menstrual cycles have been associated with lower risk of pre-menopausal breast cancer and higher risk of endometrial cancer, but associations with other malignancies are less clear.
Study Design, Size, Duration: Prospective cohort study. Prospective follow-up of 78 943 women participating in the Nurses' Health Study II between 1989 and 2015.
Participants/Materials, Setting, Methods: We followed 78 943 pre-menopausal women without cancer history who reported the usual length and regularity of their menstrual cycles at different ages (14–17, 18–22 and 29–46 years). Cancer diagnosis was confirmed through medical record review and classified as obesity-related (colorectal, gallbladder, kidney, multiple myeloma, thyroid, pancreatic, esophageal, gastric, liver, endometrial, ovarian and post-menopausal breast) or non-obesity-related. We fitted Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CIs of the association between menstrual cycle characteristics and cancer incidence.
Main Results and the Role of Chance: We documented 5794 incident cancer cases during 1 646 789 person-years of follow-up. After adjusting for BMI and other potential confounders, women reporting irregular cycles at age 29–46 years had an 11% (95% CI: 2–21%) higher risk of total invasive cancer than women reporting very regular cycles at the same age. This association was limited to obesity-related cancers, with a 23% (95% CI: 9–39%) higher risk and was strongest for endometrial cancer (HR = 1.39; 95% CI: 1.09–1.77). Findings were comparable for cycle characteristics earlier in life and for menstrual cycle length. Very irregular cycles at age 14–17 years were associated with significant increase in risk of colorectal cancer (HR = 1.36; 95% CI: 1.02–1.81).
Limitations, Reasons for Caution: Our study might be subject to recall bias for findings pertaining to cycle characteristics in adolescence and early adulthood, as these were retrospectively reported. Generalizability to non-White women may be limited, as 96% of participants were White.
Wider Implications of the Findings: Women with irregular or long menstrual cycles in mid-adulthood had a statistically significantly higher risk of developing cancer, especially obesity-related cancers. This association was not limited to gynecological cancers. Obesity-related cancers may need to be added to the spectrum of long-term health consequences of long or irregular cycles, possibly warranting targeted screening among women who experience long or irregular cycles in mid-adulthood.
Study Funding/Competing Interest: This work was supported by grants U01 CA176726, U01 HL145386 and R01 HD096033 from the National Institutes of Health. The authors have no conflicts of interest to declare.
Trial Registration Number: N/A.
Introduction
About 10–20% of women of reproductive age experience long or irregular menstrual cycles (Vollman, 1956; Chiazze et al., 1968; Real et al., 2007; Nohara et al., 2011; Toffol et al., 2014; Bull et al., 2019). Menstrual cycle regularity and length, which are tightly regulated by the hypothalamic–pituitary–ovarian axis, may be reflective of women's overall health (Diaz et al., 2006). Population-based studies have reported that irregular cycles and polycystic ovary syndrome (PCOS), the most common endocrinopathy in women and the most frequent cause of oligomenorrhea (Hart et al., 2004), are associated with hypertension (Joham et al., 2015), type 2 diabetes mellitus (Solomon et al., 2001; Wang et al., 2020), dyslipidemia (Legro et al., 2001), cardiovascular disease (Solomon et al., 2002) and premature mortality (Solomon et al., 2001; Wang et al., 2020). Often, the association between long or irregular cycles and obesity-related chronic conditions is independent of BMI and present when examined among non-obese women (Wang et al., 2020), suggesting that the endocrine milieu associated with long or irregular cycles may be responsible for these health effects above and beyond the effect of obesity itself. However, the link between menstrual cycle characteristics throughout a woman's life course and other obesity-related chronic conditions, such as obesity-related malignancies, is less clear.
Previous research has suggested that long or irregular cycles or PCOS diagnosis is associated with a higher risk of endometrial cancer and a lower risk of breast cancer, attributing this last relation to fewer cumulative lifetime ovulatory cycles and, consequently, lower lifetime exposure to progesterone and other ovarian hormones (Henderson et al., 1985; Key and Pike, 1988). However, this mechanism does not necessarily apply to all cancers. Long and irregular cycles are associated with insulin resistance, hyperandrogenism (The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2004) and chronic inflammation (Duleba and Dokras, 2012), which are in turn risk factors for other cancers (Coussens and Werb, 2002; Calle and Kaaks, 2004; Lukanova and Kaaks, 2005), particularly for obesity-related cancers (Calle and Kaaks, 2004; Lauby-Secretan et al., 2016). However, a comprehensive evaluation of the association between menstrual length and irregularity with cancer development is lacking. To address this question, we assessed the association between menstrual cycle regularity and length throughout the reproductive lifespan with risk of total invasive cancer, obesity-related cancers and non-obesity-related cancers in a prospective cohort of women who have been actively followed for over 30 years (Bao et al., 2016). We hypothesized that long or irregular cycles would be associated with a higher total cancer risk and that this association would be stronger for obesity-related cancers.
Hum Reprod. 2022;37(2):341-351. © 2022 Oxford University Press