The cardioprotective association of high-density lipoprotein cholesterol (HDL-C) may vary by menopause stage or estradiol level. We tested whether associations of comprehensive HDL metrics (HDL subclasses, phospholipid and triglyceride content, and HDL cholesterol efflux capacity [HDL-CEC]) with coronary artery calcium (CAC) score and density vary by menopause stage or estradiol level in women transitioning through menopause. Participants (N = 294; mean age [SD]: 51.3 [2.9]) had data on HDL metrics and CAC measures at one or two time points during the menopause transition. Generalized estimating equations were used for analyses. Effect modifications by menopause stage or estradiol level were tested in multivariable models. In adjusted models, menopause stage modified the associations of specific HDL metrics with CAC measures. Higher small HDL particles (HDL-P) concentrations (p-interaction = 0.008) and smaller HDL size (p-interaction = 0.02) were associated with greater odds of CAC presence in late perimenopause than in pre/early perimenopause stage. Women in the highest estradiol tertile, but not the lower tertiles, showed a protective association of small HDL-P with CAC presence (p-interaction = 0.007). Lower large HDL-P concentrations (p-interaction = 0.03) and smaller HDL size (p-interaction = 0.03) were associated with lower CAC density in late perimenopause than in postmenopause stage. Associations of HDL phospholipid and triglyceride content and HDL-CEC with CAC measures did not vary by menopause stage or estradiol level. We concluded that HDL subclasses may impact the likelihood of CAC presence and the stability of coronary plaque differently over the menopause transition. Endogenous estradiol levels may contribute to this observation.

Background: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder (NDD) characterized by inattention, hyperactivity and impulsivity, whereas autism spectrum disorder (ASD) is an NDD characterized by impaired social functioning and restricted interests and behaviors. These two NDD’s often co-occur in individuals—up to 50% of people with ASD may show significant traits of ADHD and approximately 66% of individuals with ADHD exhibit significant traits of ASD. Co-occurring symptoms of both ASD and ADHD are a risk factor for decreased quality of life in the NDD population, and more research on this intersection is needed to better serve these individuals. Study of sex hormone levels and study of brain white matter (WM) have suggested several key differences in sex hormone profiles and WM tracts among individuals with ASD, ADHD, and comorbid ASD and ADHD. People with ASD generally show higher levels of both testosterone (T) and dehydroepiandrosterone (DHEA) when compared to controls, while boys with ADHD have been shown to have lower levels of DHEA, but similar T levels, when compared with controls. Furthermore, altered sex hormone levels have been correlated with symptom severity in both individuals with ADHD and with ASD. For these reasons and more, DHEA and T are often referred to in the neurodevelopment literature as “neurosteroids.” WM tract alterations are typically investigated using diffusion tensor magnetic resonance imaging (DTI) of the head. The measure used as a proxy for WM tract integrity is fractional anisotropy (FA). Both abnormally high and low FA values have been detected in individuals with ADHD, ASD, or features of both, particularly in the tracts connecting the two cerebral hemispheres, tracts connecting multiple cortical areas, and tracts connecting the cortex and the primitive motor control center. Just as with alterations in sex hormone levels, these alterations in FA values are correlated with both ADHD and ASD symptom severity. Although one study on typically developing pubertal boys showed higher rates of increasing T were correlated with lower FA in a WM tract within the brain’s memory and emotion center, there is a gap in the literature around a potential link between neurosteroids and WM integrity in children with ADHD. Better understanding of neurosteroidal regulation of aberrant WM development in ADHD, and its relationship to both ASD and ADHD symptom severity within this population would contribute to our understanding of the ASD-ADHD intersection. Objectives: The goal of this analysis was to elucidate a relationship between the neurosteroids T and DHEA, and integrity of one or more particular WM tracts in children with ADHD. Methods: Four groups of children ages 9-11 years were compiled from the Adolescent Brain Cognitive Development Study (ABCD) via the National Database for Autism Research—males with ADHD, females with ADHD, TD females, and TD males (n=121 per group). Children with ASD, obsessive compulsive disorder, conduct disorder, and schizophrenia diagnoses were excluded. Groups were matched 1:1 by handedness and age. Groups were mean-matched by Parent Pubertal Development Scale (PDMS) item sum within sex. Group status served as the dependent variable, and the independent variables were mean FA within the 23 WM areas examined by ABCD, prepubertal salivary T concentration, prepubertal salivary DHEA concentration, number of ADHD items endorsed on DSM interview (ADHD symptom severity measure), and Parent Short Social Responsiveness Scale (SRS) sum (autistic trait severity measure). All measures were collected at the ABCD baseline visit, except for the SRS, which was conducted at the 1-year follow-up visit. Statistical analysis included two-way ANOVA’s and unpaired, two-way t-tests. The following Pearson linear regression analyses were also conducted: mean FA of each tract over each hormone, symptom severity (both ASD and ADHD) over mean FA of each tract, and symptom severity (both ASD and ADHD) over each hormone. Results: Subjects with ADHD showed significantly higher autistic traits than TD subjects. There were sex-by-diagnosis interaction effects on two tracts: the left inferior fronto-occipital fasciculus (IFOF) and the left cingulate cingulum (CGC). Both autistic trait severity and ADHD symptom severity were negatively correlated with both DHEA and T in males with ADHD, but not in females with ADHD or in TD subjects. ADHD symptom severity was positively correlated with mean FA in the frontal region of the right superior corticostriate (SCS) among all subjects with ADHD pooled (R=0.14, p=.03), whereas analysis of the females and males with ADHD separately showed a positive trend among females (R=0.15, p=.10) and a negative trend among males (R=-0.12, p=.19). TD males showed a negative correlation between DHEA and mean FA in the left SCS (R=-0.21, p=.02), which was notably absent among males with ADHD. TD females showed a positive correlation between T and mean FA in forceps major (FM) (R=0.27, p<.01), while females with ADHD showed a negative correlation between T and mean FA in FM (R=-0.22, p=.02). Conclusion: These findings reinforce the important role of low levels of DHEA in development of ADHD symptoms in boys, while highlighting that T may be a previously unknown mediator. Furthermore, low DHEA and T may play a more significant role in ADHD symptom development in boys than in girls. While higher levels of DHEA and T are linked to higher severity of autistic traits in the ASD population, these results suggest that lower levels of DHEA and T are correlated with higher autistic trait severity in boys with ADHD. This analysis supports the hypothesis that hormonal influence on ADHD symptom severity may take place via neurosteroidal regulation of development of one or more specific WM tracts, and that the anatomy and pathophysiology of this process may be sex-specific. DHEA’s role in the typical development of cortico-basal-ganglia communication may be suppressed in boys with ADHD. Aberrant regulation of interhemispheric communication development by T may be an important factor in the pathogenesis of ADHD in girls. Additionally, the opposing effects of cortico-basal-ganglia WM integrity on ADHD symptom severity in girls versus boys with ADHD, and the presence of sex-by-diagnosis interaction effects in this analysis further reinforce the hypothesis that WM differences in ADHD differ between boys and girls. This was a cross-sectional analysis of prepubescent and early pubescent subjects, therefore it is important to place any sex differences demonstrated here in the context of longitudinal neurodevelopment literature given the disparity in pubertal timing between the sexes.