Irregular and especially long menstrual cycles, particularly in early and mid adulthood, are associated with an increased risk for cardiovascular disease. This finding is demonstrated in a new analysis of the Nurses' Health Study II.
"To date, several studies have reported increased risks of cardiovascular risk factors or cardiovascular disease in connection with cycle disorders," wrote Yi-Xin Wang, MD, PhD, a research fellow in nutrition, and his team from the Harvard T. H. Chan School of Public Health in Boston, in an article published in JAMA Network Open.
Ute Seeland, MD, speaker of the Gender Medicine in Cardiology Working Group of the German Cardiology Society, told Medscape Medical News, "We know that women who have indicated in their medical history that they have irregular menstrual cycles, invariably in connection with polycystic ovary syndrome (PCOS), more commonly develop diabetes and other metabolic disorders, as well as cardiovascular diseases."
Cycle Disorders' Role
However, the role that irregular or especially long cycles play at different points of a woman's reproductive life span was unclear. Therefore, the research group investigated the associations in the Nurses' Health Study II between cycle irregularity and cycle length in women of different age groups who later experienced cardiovascular events.
At the end of this study in 1989, the participants also provided information regarding the length and irregularity of their menstrual cycle from ages 14 to 17 years and again from ages 18 to 22 years. The information was updated in 1993 when the participants were aged 29 to 46 years. The data from 2019 to 2022 were analyzed.
"This kind of long-term cohort study is extremely rare and therefore something special," said Seeland, who conducts research at the Institute for Social Medicine, Epidemiology, and Health Economics at the Charit̩ РUniversity Hospital Berlin.
The investigators used the following cycle classifications:
very regular (no more than 3 or 4 days before or after the expected date)
regular (within 5 to 7 days)
usually irregular
always irregular
no periods
The cycle lengths were divided into the following categories:
less than 21 days
21 to 25 days
26 to 31 days
32 to 39 days
40 to 50 days
more than 50 days
too irregular to estimate the length
The onset of cardiovascular diseases was determined using information from the participants and was confirmed by reviewing the medical files. Relevant to the study were lethal and nonlethal coronary heart diseases (such as myocardial infarction or coronary artery revascularization), as well as strokes.
Significant in Adulthood
The data from 80,630 study participants were included in the analysis. At study inclusion, the average age of the participants was 37.7 years, and the average body mass index (BMI) was 25.1. "Since it was predominantly White nurses who took part in the study, the data are not transferable to other, more diverse populations," said Seeland.
Over 24 years, 1816 women (2.4%) had a cardiovascular event. "We observed an increased rate of cardiovascular events in women with an irregular cycle and longer cycle, both in early an in mid-adulthood," wrote Wang and his research group. "Similar trends were also observed for cycle disorders when younger, but this association was weaker than in adulthood."
Compared with women with very regular cycles, women with irregular cycles or without periods who were aged 14 to 17 years, 18 to 22 years, or 29 to 49 years exhibited a 15%, 36%, and 40% higher risk of a cardiovascular event, respectively.
Similarly, women aged 18 to 22 years or 29 to 46 years with long cycles of 40 days or more had a 44% or 30% higher risk of cardiovascular disease, respectively, compared with women with cycle lengths of 26 to 31 days.
"The coronary heart diseases were decisive for the increase, and less so, the strokes," wrote the researchers.
Classic Risk Factors?
Seeland praised the fact that the study authors tried to determine the role that classic cardiovascular risk factors played. "Compared with women with a regular cycle, women with an irregular cycle had a higher BMI, more frequently increased cholesterol levels, and an elevated blood pressure," she said. Women with a long cycle displayed a similar pattern.
It can be assumed from this that over a woman's life span, BMI affects the risk of cardiovascular disease. Therefore, Wang and his co-authors adjusted the results on the basis of BMI, which varies over time.
Regarding other classic risk factors that may have played a role, "hypercholesterolemia, chronic high blood pressure, and type 2 diabetes were only responsible in 5.4% to 13.5% of the associations," wrote the researchers.
"Our results suggest that certain characteristics of the menstrual cycle across a woman's reproductive lifespan may constitute additional risk markers for cardiovascular disease," according to the authors.
The highest rates of cardiovascular disease were among women with permanently irregular or long cycles in early to mid adulthood, as well as women who had regular cycles when younger but had irregular cycles in mid adulthood. "This indicates that the change from one cycle phenotype to another could be a surrogate marker for metabolic changes, which in turn contribute to the formation of cardiovascular diseases," wrote the authors.
The study was observational and so conclusions cannot be drawn regarding causal relationships. But Wang and his team indicate that the most common cause of an irregular menstrual cycle may be PCOS. "Roughly 90% of women with cycle disorders or oligomenorrhea have signs of PCOS. And it was shown that women with PCOS have an increased risk of cardiovascular disease."
They concluded that "the associations observed between irregular and long cycles in early to mid-adulthood and cardiovascular diseases are likely attributable to underlying PCOS."
For Seeland, however, this conclusion is "too monocausal. At no point in time did there seem to be any direct information regarding the frequency of PCOS during the data collection by the respondents."
For now, we can only speculate about the mechanisms. "The association between a very irregular and long cycle and the increased risk of cardiovascular diseases has now only been described. More research should be done on the causes," said Seeland.
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