Long or irregular menstrual cycles in relatively young women are linked an increased risk of both prevalent and incident nonalcoholic fatty liver disease (NAFLD), according to a cross-sectional study that included data on more than 70,000 women.
“Our results indicate that menstrual irregularity, which is easier to diagnose and usually presented earlier than PCOS [polycystic ovary syndrome] highlights the possibility of identifying premenopausal women at risk of developing NAFLD,” reported a team of authors primarily from Sungkyunkwan University, Seoul, South Korea.
Dr. Seungho Ryu
The study evaluated women aged younger than 40 years who were participating in the Kangbuk Samsung Health Study, which involves a comprehensive biennial health examination at health centers in South Korea. Of the 135,090 women enrolled over a 6-year period who had at least one follow-up examination, 72,092 were available for analysis after excluding for a sizable list of confounding factors such as liver disease and infections; exposure to steatogenic medications, such as corticosteroids; hysterectomy; and pregnancy.
NAFLD prevalence climbs with longer menses
Of these women, 36.378 (27.7%) had menstrual cycles of 26-30 days and were identified as the index group. The prevalence of NAFLD in this group was 5.8%. For those with a menstrual cycle of 31-39 days, the prevalence rate climbed to 7.2%. For those with a menstrual cycle of at least 40 days or too irregular to estimate, the prevalence was 9.7%. The prevalence was 7.1% for those with a menstrual cycle less than 21 days.
The results of this study were published in the Journal of Clinical Endocrinology & Metabolism.
In those without NAFLD at baseline who were then followed for a mean of 4.4 years, there were 4,524 incident cases of NAFLD. Incidence density was calculated per 103 patient-years. In the index group, the rate was 18.4. It climbed to 20.2 for those with a menstrual cycle of 31-39 days and then to 22.9 for those with a menstrual cycle of at least 40 days. For those with a cycle of fewer than 21 days, the rate was 26.8.
After adjusting for age, body mass index, insulin resistance, and other confounders, the hazard ratio for incident NAFLD for those with long or irregular menstrual cycles compared with the incident group corresponded with a 22% increased risk (HR, 1.22; 95% confidence interval, 1.14-1.31). When calculated in a time-dependent analysis, the risk of NAFLD was increased by almost 50% (HR, 1.49; 95% CI, 1.38-1.60).
Risk persists with PCOS exclusion
PCOS has previously been associated with increased risk of NAFLD, but the association between long or irregular menstrual cycles and NAFLD persisted after women with PCOS were excluded.
The mechanism that links menstrual irregularity with NAFLD is unclear, but the investigators said that estrogen exposure is implicated. In addition to a previously reported associated between low estradiol levels and antiestrogens such as tamoxifen with increased risk of NAFLD, they cited studies associating estrogen replacement therapy with a reduced risk of NAFLD. The role of estrogen in suppressing inflammation, oxidative stress, and insulin resistance are all activities that might link more regular menses with a reduced risk of NAFLD, the authors contended.
Women older than 40 years were excluded from this analysis to reduce the possibility of perimenopausal changes as a confounding factor.
Of study limitations acknowledged by the investigators, the presence of NAFLD was diagnosed on ultrasonography rather than histology. Information on sex hormone or prolactin levels was not captured in relation to NAFLD incidence, and the lack of exposure to estrogen replacement therapy and oral contraceptives was based on self-reports from the participants.
Still, the large study size and the consistency of results after adjustment for multiple risk factors argue that long and irregular menstrual cycles do identify women at risk for NAFLD. One implication is that irregular menses can be a marker for NAFLD risk.
“Our findings do not prove a causal relationship, but they show that long or irregular menstrual cycles were significantly associated with an increased risk of developing NAFLD,” said Seungho Ryu, MD, PhD, a professor at the Sungkyunkwan University. Senior author of this study, Dr. Ryu emphasized in an interview that the association “was not explained by obesity or any other risk factor for NAFLD.”