Clinical Trial Summary
Despite significant improvements in prevention and treatment of cardiovascular disease (CVD),
the growing aging population suggests CVD will continue to pose a significant public health
burden. Women are a special group where microvascular disease is more common and traditional
risk factors may not fully identify risk. Women's reproductive history (e.g. menarcheal age,
menstrual cycles, infertility, pregnancy, menopause) may pose unique risk and suggests an
opportunity for new approaches. The investigators propose a women-centered approach for early
identification of women at risk that investigates the unique loss of reproductive function at
an age long before other vital systems fail. Despite its importance, little is known about
the determinants or correlates of ovarian aging, or the health implications, especially in
diverse communities. Only recently have reliable biomarkers of the remaining oocyte pool been
available for use in normally cycling women. This availability gives us a unique opportunity
to characterize the association between "ovarian age" (cross-sectional) and the rate of
"ovarian aging" or oocyte decline over time (longitudinal) and the health implications of
accelerated oocyte loss. The investigators hypothesize ovarian age/aging provides a window
onto the general health of women. The investigators suggest it is not the progressive
deficiency of estrogen with menopause that increases risk, but common underlying cellular
aging mechanisms first evident in young populations as lower ovarian reserve (follicle
number) due to the unique sensitivity of the ovary.
Studies of cellular aging focused on mitochondrial dysfunction, oxidative stress,
inflammation, and telomere length have identified correlations with CVD risk. Improved
understanding of the mechanisms of cellular aging suggests telomere shortening and
dysfunction may drive mitochondrial dysfunction and potentially the parallel between cellular
aging and CVD. The oocyte is particularly sensitive to mitochondrial dysfunction, having 10
times the number of mitochondria as any somatic cell. Additionally, mitochondrial dysfunction
and telomere shortening have been associated with ovarian aging. This begs the question of
whether, given the susceptibility of the ovary to mitochondrial dysfunction, accelerated
ovarian aging may be a harbinger of subsequent CVD risk. To address this critical question,
the investigators propose to leverage the largest and most ethnically diverse population of
normal reproductive-aged women, with detailed measures of ovarian age, and to deploy
peripheral endothelial function testing, a non-invasive sensitive marker of early CVD risk.
Ovarian aging is thought to be largely genetically determined, but the impact of
race/ethnicity has not been fully explored. Evaluating the impact of ethnicity on ovarian
aging, and combining this information with the impact of modifiable behavioral risk factors,
may help clarify CVD risk in young, ethnically-diverse, reproductive-age women. The
investigators believe improving our understanding of factors that affect the rate of
oocyte/follicle loss and the relationship with CVD risk factors will promote a novel method
to identify women at earlier and/or increased cardiac risk.
The investigators propose to carry out three Specific Aims:
1. Determine whether markers of ovarian age/aging are associated with increased CVD risk.
Specifically, the investigators propose to assess whether:
1. Ovarian age predicts CVD risk (measured by peripheral endothelial function testing)
independent of chronological age.
2. The rate of ovarian aging is independently associated with increased CVD risk after
adjustment for ovarian and chronological age.
2. Determine whether ovarian aging may moderate or mediate established associations between
race/ethnicity and CVD risk and socio/emotional health and CVD risk. Specifically, the
investigators propose to:
1. Examine whether observed race/ethnic disparities in CVD risk (measured by
peripheral endothelial function testing) may vary by (moderation model) or be
partially attributable to (mediation model) ovarian aging.
2. Examine whether effects of socio/emotional health (as indexed by separate
composites of psychosocial functioning and socioeconomic status) on CVD risk may
vary by (moderation model) or be partially attributable to (mediation model)
ovarian aging.
3. Determine if similar mechanisms of cellular aging underlie both ovarian aging and CVD
risk. Temporal appearance of indices of cellular aging, ovarian aging and CVD risk would
support our primary hypothesis. Specifically, we propose to determine whether telomere
and mtDNA in peripheral leukocytes, oxidative stress (plasma F2-isoprostanes), and
indices of inflammation (C-reactive protein, interleukin-6, and soluble intercellular
adhesion molecule-1) correlate with both ovarian aging and CVD risk, and the temporal
pattern of appearance.
