Irregular Periods Linked to Type 2 Diabetes in Teenage Girls

Menstrual irregularity is more common in adolescents with recent-onset type 2 diabetes compared with healthy girls of a similar age, according to the first study to examine sex steroids and menstrual health in a large cohort of obese girls.

Results also show that irregular menses were associated with higher body mass index (BMI) (P = .001), testosterone (P = .01), and aspartate aminotransferase (AST) levels (P = .001), and lower estradiol concentrations. However, menstrual dysfunction was not associated with alterations in insulin sensitivity or beta-cell function, nor did it improve with 2 years of antihyperglycemic treatment.

Data were drawn from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, which reflects the increasing incidence of the disease in young people.

"The 20.5% frequency of irregular menses in the TODAY girls who are at least 1 year post-menarche appears to be higher than in the general adolescent population, although reported prevalence of irregular menses in normal adolescents varies widely," noted lead author Megan Kelsey, MD, a pediatric endocrinologist from the University of Colorado, Aurora, in a press release by the Endocrine Society.

Highlighting the importance of understanding the association between type 2 diabetes and menstrual irregularities, Kelsey pointed out that "infrequent periods can be associated with heavy and painful periods, increased risk for fatty liver disease, fertility problems, and long-term increased risk for endometrial cancer."

Reflecting on the lack of effect from glucose-lowering treatment, she added that "...girls with youth-onset diabetes may need...additional intervention above and beyond their diabetes treatment to improve their menstrual health."

The results were published online April 24 in the Journal of Clinical Endocrinology and Metabolism.

Filling a Research Gap in Teenage Girls With Type 2 Diabetes

Participants in the TODAY study had received a diagnosis of type 2 diabetes in the past 2 years and were required to have an HbA_1c of less than 8%. The study compared the efficacy of three treatment arms: metformin alone; metformin plus rosiglitazone; and metformin plus an intensive lifestyle intervention. Because there was a run-in period, many of the participants were already on metformin alone at baseline.

The main results of TODAY were previously reported in 2012 (N Engl J Med. 2012;366:2247-2256), and further findings were published a year later in a series of articles in Diabetes Care, as reported by Medscape Medical News.

This new secondary analysis by Kelsey and colleagues aimed to fill a research gap by assessing the frequency of menstrual irregularity in girls with recently diagnosed diabetes and whether the addition of intensive lifestyle or rosiglitazone to previous treatment with metformin helped to improve symptoms.

As such, the analysis aimed to assess the frequency of menstrual dysfunction (defined as fewer than three periods in the prior 6 months); compare metabolic and hormonal characteristics in girls with and without menstrual dysfunction; assess the effect of treatment on menstrual function; and finally, evaluate associations of sex steroids with estimates of insulin sensitivity and secretion.

Participants included in the current analysis were not on hormonal contraception, had a BMI above the 85th percentile, were at least 1-year post-menarche, and an average age of 14 years. Self-reported menstrual history was assessed retrospectively.

A total of 79.5% of girls reported having regular menses, and 20.5% had an irregular menstrual cycle. The latter had greater metabolic dysfunction, as indicated by higher BMI, waist circumference, and liver transaminases (including AST). There were no significant differences in mean insulin sensitivity between the two groups.

Notably, TODAY girls with irregular menses had significantly higher total testosterone despite significantly lower sex hormone binding globulin (SHBG), free androgen index, and estradiol levels. These differences persisted after adjustment for BMI. Elevated testosterone is a hallmark of the diagnosis of PCOS, the authors add.

However, not all the TODAY girls with irregular periods had elevated testosterone, suggesting other causes for menstrual dysfunction.

Kelsey and colleagues point out that "it is difficult to quantify how much of this menstrual irregularity is related to obesity alone, due to the lack of an obese nondiabetic comparison group." They also note that "the prevalence rate of menstrual dysfunction in obese nondiabetic girls is not well-studied."

Treatment Regimens Had No Effect on Menstrual Irregularity

No significant effects of treatment groups on menstrual irregularity were seen between baseline, 12, and 24 months of therapy.

In addition, the authors note that the fact that 80% of the TODAY girls were on a maximum metformin dose at baseline means that the girls who also had PCOS would be considered treated at that time (metformin is also a treatment for PCOS).

"This may have masked some of the menstrual dysfunction that would have been present if the girls had been untreated," they observe.

"Further studies are needed to better understand the role of reproductive hormones on sex differences in the pathophysiology of type 2 diabetes in youth," they conclude.

Kelsey is a site principal investigator for Merck and Daiichi-Sankyo. Disclosures for the other authors are listed in the article.

J Clin Endocrinol Metab. Published online April 24, 2018. Abstract

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