Irregular adolescent menstrual cycles and associated risks in young adults

By: Danielle Coleman, DO

Editor’s Note: To mark American Heart Month, we are featuring research that assessed the relationship between irregular menstrual cycles of school-aged women and obesity, summarized by Danielle Coleman, a former FACTS elective participant. This 2011 study published in Fertility and Sterility [1] could be expanded to examine coronary heart disease, as well, especially given the established correlation between irregular menstrual cycles and an increased risk for coronary heart disease and type 2 diabetes.

Introduction

Existing research has established a correlation between irregular menstrual cycles and an increased risk for both coronary heart disease and type 2 diabetes in adult women.[2-6]  The degree of irregularity or deviation from the standard cycle that may have clinical significance has yet to be defined, but a tool utilizing such information would serve as an instrument for clinicians to better assess long-term risk for obesity, endocrinopathies, and cardiovascular disease from an early age. Researchers Morrison et al. aimed to do just that, analyzing annual data obtained from patients in late adolescence, when interventions may arguably be the most effective.[1]

“Existing research has established a correlation between irregular menstrual cycles and an increased risk for both coronary heart disease and type 2 diabetes in adult women.”

Methodology

Researchers utilized a cohort of school-aged females previously assembled by the National Heart, Lung, and Blood Institute in a 10-year longitudinal, multicenter study focused on the development of obesity in white and black adolescent females. Baseline measures of fasting insulin, sex steroid hormones and sex hormone binding globulin (SHBG), lipid profiles, glucose, apolipoprotein A1, and blood pressure were collected in the early parts of the study. At annual follow-up visits, the researchers assessed sexual maturation, onset of menarche, days since previous menstrual cycle and pregnancy status.

This study focused on a subset of 370 participants who had at least five years of annual reports on their menstrual cycles. These individuals were then further prospectively assessed for obesity and endocrine dysfunction at age 25 based on measures of insulin, glucose, insulin resistance (IR), body mass index (BMI), and waist circumference. Any patients who were diagnosed with type 1 diabetes or had early elevated fasting blood glucose levels were excluded from the study.

Researchers applied the definition for oligomenorrhea, previously described by Hoof et al. [8][9] as a menstrual cycle lasting ≥42 days, based on their findings of an association of ≥42-day cycles with hyperandrogenism and polycystic ovarian syndrome (PCOS).

Then, researchers analyzed the raw data with a number of statistical methods, including the Spearman correlation, stepwise regression, Benjamini-Hotchberg procedure, and Mantel-Haenszel test. Researchers worked to identify statistically significant correlations and decrease the false discovery rate.

Results

Of the 320 participants, just over 30% had at least one annual report with one or more episodes of delayed menstrual cycles. For those participants with more than one delayed cycle, the majority of them had occurred sequentially.

Participants who experienced ≥3 oligomenorrhea reports had increased levels of DHEA-S and Free Testosterone at 14 and 19 years of age, compared to other study participants. These individuals also had higher BMI and waist circumference measurements at age 14, 19, and 25; higher glucose and HOMA-IR levels at 24; and higher insulin levels at 25, compared to the rest of the cohort.

After statistical analysis, a positive correlation was identified between the annual number of menstrual cycles ≥42 days and increases in body weight, waist circumference, and BMI between 14 to 19 years of age. Oligomenorrhea was inversely correlated with HDLC changes in that same time frame. There were no statistically significant associations with changes in LDLC, triglycerides, insulin, glucose, or insulin resistance measures from the study’s onset to its end.

“A positive correlation was identified between the annual number of menstrual cycles ≥42 days and increases in body weight, waist circumference, and BMI between 14 to 19 years of age.”

Oligomenorrhea from age 14 to 19 was a significant positive explanatory variable for body weight, waist circumference, and BMI changes from 14 to 25 years old. It was also a significant negative explanatory variable for change in HDLC. Age of menarche was inversely related to a change in waist circumference. Lastly, a change in BMI was a significant explanatory variable for those with one or fewer reports of delayed menstruation.

Discussion

The study’s central findings centered around the association between irregular menstrual cycles with biomarkers of dysglycemia and risk factors for cardiovascular disease. The study participants who had ≥3 annual reports of oligomenorrhea (menstrual cycles ≥42 days) in late adolescence had significantly increased BMI, centralized fat patterning, fasting insulin, and glucose and HOMA-IR by their mid-twenties. For those between 14 and 19 years of age, there were higher free T and DHEA-S levels than their peers with fewer oligomenorrheic reports. This study’s findings suggest that by identifying menstrual cycle irregularity early in a person’s reproductive life, we may be able to implement measures early enough to prevent the development of type 2 diabetes in young adulthood.

“By identifying menstrual cycle irregularity early in a person’s reproductive life, we may be able to implement measures early enough to prevent the development of type 2 diabetes in young adulthood.”

Elevated androgens and irregular menses have been previously associated with cardiovascular events in post-menopausal women. This study indicates that androgen levels are already significantly increased in people with irregular cycles by their late adolescence. This may be useful in identifying at-risk individuals early enough for preventative measures, but more research needs to be done to better identify a causative relationship for cardiovascular disease.

Change in BMI was independently a significant positive correlate for those with one or fewer reports of oligomenorrhea. Leading researchers suggest that using BMI as a singular variable may help us to better screen for oligomenorrhea in obese women. Furthermore, individuals with PCOS, particularly hyperandrogenic PCOS, often have a combination of the aforementioned variables and episodes of oligomenorrhea and may be better identified utilizing menstrual charting methods in the first decade after menarche.[10][11]

Strengths of this study include the study design, which is an impressive 10-year prospective study with an additional 5-year follow-up. The large cohort of data was collected by a standardized group of trained clinicians in an effort to control for bias.

One limitation identified by the researchers was the lack of detailed information pertaining to the participants’ menstrual cycles outside of the annual reports on cycle timing. The responses were also elicited with very superficial questioning techniques, which they felt may have increased the number of false negatives. The data could be qualitatively and quantitatively improved by teaching participants to chart their cycles using any combination of fertility awareness methods to better tease out the nuances of their “delayed” menstrual cycles and increase the accuracy of the collected data.

Another limitation, not listed by the researchers, is in regards to participant selection: The original study cohort excludes a number of racial backgrounds, including Hispanics who have a higher rate of hyperandrogenic PCOS.

There is a great deal of insight to be gained into the usefulness of teaching cycle charting using fertility awareness-based methods in the first few years after menarche. FABMs can aid in the early diagnosis of reproductive health conditions, such as PCOS and endometriosis. This could guide early interventions and treatment discussions that have major morbidity and mortality implications for the future. It would be useful for clinicians if this research were expanded to identify the number of cases of coronary heart disease — which develop in this same cohort — and assess whether early interventions or preventative therapy might reduce that risk. A similar study in a more diverse patient population that incorporates FABM charting could also provide more specific and accurate data.

Sources

[1] Morrison JA, Glueck CJ, Daniels S, Wang P, Stroop D. Ramifications of adolescent menstrual cycles ≥42 days in young adults. Fertil Steril. 2011;96(1):236-240.e1. doi:10.1016/j.fertnstert.2011.04.005
[2] Atsma F, Bartelink ML, Grobbee DE, Rutten A, Bots ML, Prokop M, et al. Reproductive factors, metabolic factors, and coronary artery calcification in older women. 2008;15:899–904.
[3] Haver MC, Locksmith GJ, Emmet E. Irregular menses: an independent risk factor for gestational diabetes mellitus. Am J Obstet Gynecol. 2003;188:1189–91.
[4] Strowitzki T, Capp E, von Eye Corleta H. The degree of cycle irregularity correlates with the grade of endocrine and metabolic disorders in PCOS patients. Eur J Obstet Gynecol Reprod Biol. 149:178–81.
[5] Souza FA, Dias R, Fernandes CE, Pimentel F, Dias D. Menstrual irregularity: a possible clinical marker of metabolic dysfunction in women with class III obesity. Gynecol Endocrinol. 2010;26:768–72.
[6] Engmann L, Jin S, Sun F, et al. Racial and ethnic differences in the polycystic ovary syndrome metabolic phenotype. Am J Obstet Gynecol. 2017;216(5):493.e1-493.e13. doi:10.1016/j.ajog.2017.01.003
[7] van Hooff MH, Voorhorst FJ, Kaptein MB, Hirasing RA, Koppenaal C, Schoemaker J. Insulin, androgen, and gonadotropin concentrations, body mass index, and waist to hip ratio in the first years after menarche in girls with regular menstrual cycles, irregular menstrual cycles, or oligomenorrhea. J Clin Endocrinol Metab. 2000;85:1394–400
[8] van Hooff MH, Voorhorst FJ, Kaptein MB, Hirasing RA, Koppenaal C, Schoemaker J. Polycystic ovaries in adolescents and the relationship with menstrual cycle patterns, luteinizing hormone, androgens, and insulin. Fertil Steril. 2000;74:49–58.
[9] Glueck CJ, Aregawi D, Winiarska M, Agloria M, Luo G, Sieve L, et al. Metformin-diet ameliorates coronary heart disease risk factors and facilitates resumption of regular menses in adolescents with polycystic ovary syndrome. J Pediatr Endocrinol Metab. 2006;19:831–42.
[10] Glueck CJ, Morrison JA, Wang P. Insulin resistance, obesity, hypofibrinolysis, hyperandrogenism, and coronary heart disease risk factors in 25 preperimenarchal girls age < or = 14 years, 13 with precocious puberty, 23 with a first-degree relative with polycystic ovary syndrome. J Pediatr Endocrinol Metab. 2008;21:973–84.
[11] Chhabra S, Venkatraman S. Menstrual dysfunction in rural young women and the presence of polycystic ovarian syndrome. J Obstet Gynaecol. 2010;30:41–5.

ABOUT THE AUTHOR

Danielle Coleman, DO

Danielle Coleman, DO, is a recent graduate from Rocky Vista University. She is currently completing a preliminary general surgery internship at the University of Colorado with plans to transition into an obstetrics & gynecology residency program. She enrolled in FACTS to better understand the multiple factors that influence the menstrual cycle and better educate her patients in managing their reproductive concerns.