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The Longitudinal Evaluation of Ovarian Aging and Cardiovascular Risk (OVACV)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03825120
Recruitment Status : Enrolling by invitation
First Posted : January 31, 2019
Last Update Posted : June 18, 2021
Sponsor:
Collaborator:
National Institute on Aging (NIA)
Information provided by (Responsible Party):
University of California, San Francisco

Brief 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.


Condition or disease
Infertility Cardiovascular Risk Factor

Detailed Description:

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.

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Study Type : Observational
Estimated Enrollment : 865 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: The Longitudinal Evaluation of Ovarian Aging and Cardiovascular Risk
Actual Study Start Date : August 15, 2018
Estimated Primary Completion Date : May 2022
Estimated Study Completion Date : May 2022

Resource links provided by the National Library of Medicine


Group/Cohort
Women from original OVA cohort



Primary Outcome Measures :
  1. Change in the EndoScore or reactive hyperemia ratio, an index of peripheral endothelial function, as assessed by the FDA-approved EndoPAT 2000 [ Time Frame: 2 times, once at each of 2 study visits ~1 year apart ]
    Endothelium-mediated changes in vascular tone will be represented by the EndoScore or ratio of Reactive Hyperemia pre-occlusion to post-occlusion of the brachial artery (via blood pressure cuff). A score > 1.67 is considered "normal" and a score <= 1.67 is "abnormal". The EndoPAT 2000 machine will be used for this measure, which is the only non-invasive method of measuring endothelial function or the state of arterial health. Well-functioning arteries protect blood vessels from hardening (or atherosclerosis) and plaque build up. The EndoScore score will be the primary measure for cardiovascular (CV) disease risk, as actual CV event rates will be too low for many years


Biospecimen Retention:   Samples With DNA
blood and urine


Information from the National Library of Medicine

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Ages Eligible for Study:   35 Years to 55 Years   (Adult)
Sexes Eligible for Study:   Female
Sampling Method:   Non-Probability Sample
Study Population
  • member of Northern California Kaiser Permanente Health Plan at time of enrollment into original OVA cohort
  • self-identifying as Caucasian, Chinese, Filipino, African-American, or Hispanice (Mexican or Central American)
Criteria

Inclusion Criteria:

  • Enrollment into the original OVA cohort (NCT00501800)

Exclusion Criteria:

  • Not a member of the original OVA cohort

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03825120


Locations
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United States, California
University of California, San Francisco
San Francisco, California, United States, 94115
Sponsors and Collaborators
University of California, San Francisco
National Institute on Aging (NIA)
Investigators
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Principal Investigator: Marcelle I Cedars, MD University of California, San Francisco
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Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03825120    
Other Study ID Numbers: R01AG053332 ( U.S. NIH Grant/Contract )
1R01AG053332-01A1 ( U.S. NIH Grant/Contract )
First Posted: January 31, 2019    Key Record Dates
Last Update Posted: June 18, 2021
Last Verified: June 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of California, San Francisco:
reproductive health
fertility
infertility
aging
health
cardiovascular disease
cardiovascular disease risk
Additional relevant MeSH terms:
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Infertility