October 1, 2020

expert reaction to study looking at menstrual cycle length and regularity and risk of early death

Research, published in The BMJ, looked at menstrual cycle length and regularity and risk of early death.

Prof Wiebke Arlt, Institute of Metabolism and Systems Research, University of Birmingham, said:

“This study is of high quality and based on a large number of individuals followed longitudinally in the Nurses Health Study II.

“The authors of the article state that “In our present study, the association of irregular and long menstrual cycles with higher risk of premature mortality persisted when we excluded women with hirsutism…., indicating that these relations were not solely driven by PCOS.” In my opinion this is an incorrect statement as both irregular menstrual cycles and hirsutism (increased male pattern body hair growth) are cardinal features of PCOS. Male hormone excess is present in more than 90% (and some argue in all) women with PCOS but only some affected women suffer from hirsutism.

“We and others have shown that women with PCOS have an increased risk of type 2 diabetes, hypertension and fatty liver disease and that the risk of these conditions increases in line with the severity of the male hormone excess. Diabetes, high blood pressure and fatty liver disease are major risk factors for cardiovascular disease, which was identified as the major cause of the increased rate of premature deaths in the BMJ study. Therefore, if those women in this study with irregular menstrual cycles are suffering from PCOS which is a strong possibility, then this could explain the association with increases cardiovascular risk.

“Male hormones and insulin resistance are indicators of possible PCOS. However, in the BMJ study both male hormones and insulin were not measured systematically, thus we cannot say with certainty whether they are related to the increased risk of premature death in the women with irregular cycles as reported in this study. This would be an obvious next step if possible for the authors of the current or future studies.

“Women who have irregular cycles should see their GP to be assessed for a diagnosis of PCOS; if required, they can also see an endocrinologist (hormone specialist) and/or a gynaecologist for further specialist advice.”

Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, said:

“The study is clearly reported and has the inevitable limitations of observational studies, but randomised studies cannot be done in this field. It is by no means certain that the association between irregular menstrual cycles and early death is a causal one, there are a number of factors, some of which are discussed by the authors. For example, there may be reverse causation with some other factors – underlying but undetected conditions might well lead to irregular cycles.

“Some of the discussion of possible mechanisms assumes causal relationships and may be simply speculation.

“The finding on oral contraceptives needs a separate study to be able to investigate that association, which may have different confounding factors some of which may be unmeasured.

“In spite of the limitations, even if the association is not causal, it is of importance for the health care of those with irregular cycles, especially those that persist, and it may be a good reason for careful monitoring of such patients. The final paragraph of the paper is reasonable though not necessarily helpful by not being specific enough as to what to do –‘Our results emphasize the need for primary care providers to include menstrual cycle characteristics throughout the reproductive years as additional vital signs in assessing women’s general health status and point to potential  lifestyle interventions to manage risk among women with menstrual cycle disorders that might have long term adverse health consequences.’”

Dr Abigail Fraser, Reader in Epidemiology, University of Bristol, said:

“This high quality study adds to a growing body of work demonstrating that indicators of women’s reproductive health reflect underlying, general health and risk of chronic disease in later life.  

“The authors have accounted for multiple potential confounders and have been very measured in their interpretation. However, they do not adjust for socio-economic position (in childhood or adulthood), which could be confounder and this is a limitation. The supplemental tables were not provided so I could not look at this in detail but it is somewhat strange that authors report associations with death from external causes as I cannot think of a biologically plausible mechanism for this other than a socio-economic one.

“This study is important because menstrual characteristics as well as women’s health in pregnancy – as another example – are easily measured and manifest relatively early on in life, providing a timely opportunity to intervene.

“This research demonstrates that it is important to study sex-specific factors as they may provide clues into causes of disease.”

Dr Jacqueline Maybin, Senior Research Fellow and Consultant Gynaecologist at the MRC Centre for Reproductive Health, University of Edinburgh, said:

“This paper reports an increased risk of early death in nurses with persistently irregular menstrual cycles verses those with regular periods. 79 505 women were included in the study and 1975 premature deaths occurred.

“The methods used are sound and authors have accounted for confounders, such as oral contraceptive use, diet, BMI and smoking. However, all of the participants in this study were nurses, some of whom will have worked very irregular hours. Shift work, particularly nightshifts, has been shown to have a significant impact on long-term health. Disruption of the circadian rhythm has also been shown to affect menstrual regularity, with shift-workers more likely to have irregular and long menstrual cycles. This was not accounted for in the analysis and may limit the application of these findings to the general population.

“The findings reported are interesting but it should be stressed that this is an association between irregular menstrual cycles and early death. This means that there is no current evidence that having irregular cycles causes early death and the association may be due to chance.

“It is also important to remember that irregular menstruation is a symptom and not a diagnosis. Therefore, a specific underlying cause of irregular menstruation may increase the risk of premature death, rather than the irregular bleeding, per se. We already know that women with polycystic ovarian syndrome (PCOS), a leading cause of irregular periods, have an increased risk of diabetes, high blood pressure and cancer of the womb. It is important that women with PCOS speak to their doctor to reduce these risks.

“This study is a real step forward in closing the data gap that exists in women’s health. It raises many interesting research questions and areas of future study. These data will encourage future interrogation of menstrual symptoms and pathologies as an indicator of long-term health outcomes and may provide an early opportunity to implement preventative strategies to improve women’s health across the lifespan.” 

Prof Adam Balen, Royal College of Obstetricians and Gynaecologists Spokesperson on Reproductive Medicine and past chair of the British Fertility Society, said:

“This is a very interesting study of a very large cohort of women which shows that a history of having had an irregular menstrual cycle is associated with an increased risk of premature mortality (death before age 70 years). A number of associations were reported including a higher body mass index, hypertension, a high blood cholesterol and smoking amongst others.

“Most interesting was an eight fold increase rate of hirsutism (that is unwanted hair growth on the face and body) in those with premature mortality. Hirsutism and irregular menses are features of polycystic ovary syndrome (PCOS) which is the commonest hormone disturbance in women and affects approximately 10-12% of the female population worldwide and leads to increased production of the androgen hormones (predominantly testosterone) from the ovaries. For many years PCOS has also been known to be associated with an increased level of markers of metabolic and cardiovascular risk.

“The important point illustrated by this study is that menstrual regularity and reproductive health provides a window into overall long term health and measures to improve the health and wellbeing of young women with an irregular menstrual cycle may also enhance lifelong health. Therefore young women with irregular periods need a thorough assessment not only of their hormones and metabolism but also of their lifestyle so that they can be advised  about steps that they can take which might enhance their overall health.”

Prof Rachel Tribe, Professor of Maternal and Perinatal Sciences, Kings College London, said:

“This substantial study is well controlled and analysed. It makes interesting and potentially important links between menstrual cycle length and future lifespan related to cardiovascular health.

“As menstrual irregularities can be a sign of hormonal conditions that are also associated with cardiovascular disease, for example polycystic ovary syndrome, it is difficult for the authors to make causal links and this study can only establish a correlation.

“This study should not be a cause of concern for all young women with irregular and/or long menstrual cycles as there are many other factors involved, but I would hope that the information would raise awareness and encourage healthcare providers (as well as women) to investigate irregular menstrual cycles; an approach that has potential to improve reproductive health and subsequent longer term outcomes.

“Limitations of the study were identified by the authors, particularly the predominance of white women in the cohort, so going forward it is important to make sure that the findings are generalizable for all women. Also there was no mention of how obstetric events could have influenced outcomes. Preeclampsia, gestational diabetes and hypertension in pregnancy are also associated with increased risk of cardiovascular disease in later life.”

Dr Kim Jonas, Lecturer in Reproductive Physiology, King’s College London, said:

“This is an interesting paper, but it is perhaps not that surprising to see an association between irregular and long menstrual cycles and earlier death given the known link between oestradiol (the main oestrogen hormone in women) levels, menopause and cardiovascular disease. As this is an observational study it cannot establish causality, just correlation.

“What this study will hopefully achieve is to raise awareness about menstrual irregularity, increase education and encourage women and doctors to consider the menstrual cycle when assessing health. However, this study does not mean that all women who have experienced irregular menstrual cycles should be concerned. There is a lot more research to be done in this area and many factors are likely to be at play.

“In terms of medical history which may have played a role in the findings, many of the women with irregular menstrual cycles had a history of hormonal-linked issues including endometriosis (endometrial tissue growing outside of the uterus) and fibroids (non-cancerous tumours that grow on the uterus), and hirsutism (excessive growth of hair in a male-like pattern), but it would have been useful to know directly about Polycystic ovary syndrome. This was self-reporting, so hirsutism to someone with dark hair would be much more noticeable and acute than someone with a fairer completion. A concern is everything seemed to be gathered through a self-reporting questionnaire and therefore may be of limited reliability, but the authors do address this in the discussion.”

‘Menstrual cycle regularity and length across the reproductive lifespan and risk of premature mortality: prospective cohort study’ by Wang et al. was published in The BMJ at 00:01 UK time on Thursday 1^st October.

DOI: 10.1136/bmj.m3464

Declared interests

Prof Wiebke Arlt: “My research is funded by the Wellcome Trust (Wellcome Investigator Award DAISY-PCOS). I serve on a scientific advisory board on women’s health for Bayer.”

Prof Stephen Evans: “No conflicts of interest.  I am funded (1 day/week) by LSHTM.  They get funding from various companies, including Astra Zeneca and GSK but I am not funded by them, I have no involvement in obtaining funding from them and I am not an investigator or any grants obtained from them.  I am the statistician to the “meta-Data Safety and Monitoring Board” for CEPI.  I will probably be paid for my attendance at meetings and expenses for travel.”

Dr Abigail Fraser: “I wish to declare that I work with and have published with several of the authors.”

Dr Jacqueline Maybin: “ None”

Prof Adam Balen: “I have no conflicts”

Prof Rachel Tribe: “No interests/conflicts to declare related to this study”

Dr Kim Jonas: “No declarations of interest to declare”