Evidence of early subclinical atherosclerosis in women with exercise-induced hypothalamic amenorrhea

Abstract STUDY QUESTION Do women with exercise-induced functional hypothalamic amenorrhea (Ex-FHA) have an increased risk of subclinical atherosclerosis, as measured by carotid intima-media thickness (cIMT)? SUMMARY ANSWER Women with Ex-FHA appear to show greater cIMT than non-exercising control women (nonEx-control). WHAT IS KNOWN ALREADY Long-term cardiovascular risk is a major concern in women with functional hypothalamic amenorrhea who exercise regularly. Although hypoestrogenic women with Ex-FHA consistently exhibit markers of risk, such as endothelial dysfunction, evidence of atherosclerosis is lacking. STUDY DESIGN, SIZE, DURATION From 2019 to 2025, we conducted a cross-sectional comparative study of five groups of premenopausal adult women (N = 50). According to our calculations, this sample size allowed us to detect a minimum difference of 0.019 mm in common cIMT between any pair of groups, setting α to 0.05 and power (1−β) to 0.80. PARTICIPANTS/MATERIALS, SETTING, METHODS We included three groups of women with different mechanisms of ovulatory dysfunction: women with Ex-FHA, women with classic PCOS, and women with non-hyperandrogenic PCOS. Healthy exercising (Ex-control) and nonEx-control served as control groups. Smokers were excluded. All women received a comprehensive cardiometabolic phenotyping including anthropometrics, circulating sex steroids, carbohydrate metabolism and lipid profiles, office and 24-hour ambulatory blood pressure monitoring, and cardioautonomic function studies. Ultrasound measurement of mean cIMT served as a marker of subclinical carotid atherosclerosis. MAIN RESULTS AND THE ROLE OF CHANCE Women with Ex-FHA were the only subgroup of study participants showing higher cIMT values than nonEx-controls [cIMT: 0.514 ± 0.057 vs. 0.411 ± 0.054 mm, respectively; mean difference: 0.103 (95%CI: 0.031; 0.175); P = 0.002]. This difference remained after adjusting for body mass index. Regarding carbohydrate and lipid metabolism, women with Ex-FHA showed a higher insulin sensitivity index than both subgroups of women with PCOS. Individuals with Ex-FHA had higher concentrations of HDL-cholesterol, HDL-triglycerides, and large- and medium-HDL particles than both subgroups of women with PCOS, Ex-controls, and nonEx-controls. Women with Ex-FHA presented with a lower resting heart rate than participants with classic PCOS, Ex-controls, and nonEx-controls. They also showed a lower diastolic blood pressure response to standing than nonEx-controls. LIMITATIONS, REASONS FOR CAUTION The limited sample size of our study population precluded us from identifying the main determinants of subclinical atherosclerosis in each subgroup of women. The cross-sectional observational design of this study does not allow causal inference regarding associations between independent variables and cIMT. Lastly, multiple comparisons may have led to spurious associations in some cases, despite having implemented rigorous adjustments for multiplicity whenever possible. WIDER IMPLICATIONS OF THE FINDINGS Whilst data on robust endpoints of women with Ex-FHA are lacking, this novel finding on subclinical carotid atherosclerosis may enhance scientific understanding of their cardiovascular risk profile. Still, larger confirmatory studies are needed with the aim of establishing cIMT as an early marker of atherosclerosis in Ex-FHA and, secondly, clarifying which intrinsic risk factors underlie this association. STUDY FUNDING/COMPETING INTEREST(S) This research was funded by Instituto de Salud Carlos III grants PI1801122 and PI2100116, and co-funded by the European Union. The authors declare not to have any conflict of interest. TRIAL REGISTRATION NUMBER ClinicalTrials.gov ID: NCT03841981