Premature cardiovascular disease (CVD) is the leading cause of death in young women. While death rates from CVD have declined in all other age groups, they are continuing to increase in women between the ages of 35 and 44 years and traditional CVD risk factors are not capturing this risk, leaving much unexplained. Prior research has demonstrated that irregular menstrual cycling in young women poses up to a 50% increased CVD risk. Women with Turner's syndrome, a genetic defect resulting in prolonged hypoestrogenemia (HypoE) from birth, have premature deaths due to accelerated CVD. Additionally, HypoE of hypothalamic origin has been associated with premenopausal obstructive coronary artery disease in women with signs and symptoms of ischemia. Taken together these data indicate that HypoE in premenopausal women is associated with accelerated CVD; and the mechanism(s) for these associations are unknown. It is established that immune- mediated inflammation plays a role in atherosclerosis, and estrogen has immunomodulatory effects resulting in suppression of pro-inflammatory cytokines while increasing anti-inflammatory cytokines. Furthermore, there is a large body of literature that demonstrates increased proinflammatory cytokines during estrogen loss after menopause. We hypothesize that HypoE in premenopausal women is associated with pre-clinical CVD, and that estrogen-mediated increases immune-mediated inflammation is a mechanistic pathway. We plan to: 1) investigate the relationship between HypoE, vascular function and preclinical CVD; 2) investigate the relationship between HypoE and immune-mediated inflammation; 3) evaluate in a randomized, double-blinded, placebo-controlled trial the impact of 4 weeks of transdermal estradiol followed by 2 weeks of estrogen plus progesterone in women with HypoE on vascular function and immune-mediated inflammation. Our study is important because it has the potential to identify a novel CVD risk factor in young women as well as an associated immune-mediated pathway. It is estimated that up to 34% of premenopausal women have secondary amenorrhea resulting in HypoE, that is 1.62 million US women between the ages of 18 and 44 years, making it more common etiology for menstrual cycle disruption than polycystic ovary syndrome. The American Academy of Pediatrics and the American College of Obstetrics and Gynecology have advocated that the menstrual cycle should be considered a vital sign due to the importance of estrogen on tissues throughout the body. For example, it has already well-established that HypoE in premenopausal women results in early-onset osteoporosis and that the immune response related to this osteoporosis is altered. This K23 application also addresses the important need to train qualified clinical investigators with the skills to work with experts related to vascular biology, atherosclerosis, immunology, and clinical trial design. The goal is to build on the applicant's experience in biostatistics, women's health and endogenous and exogenous estrogen by acquiring additional skills required for a successful independent clinical research career.

Public Health Relevance

This application for Chrisandra Shufelt MD, MS incorporates a multi-disciplinary, mentored patient-oriented research and career development plan to prepare her for independent, translational investigation in women's health and cardiovascular disease. The research project aims to investigate endothelial function, pre-clinical atherosclerosis, and immune-mediated inflammation as mechanistic pathways in premenopausal women with hypoestrogenemia compared to ovulatory eumenorrheic women. This project will be highly significant in leading to new lines of research on discovery of novel, alternative testing as well as treatment modalities in premenopausal women.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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NHLBI Mentored Patient-Oriented Research Review Committee (MPOR)
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Wang, Wayne C
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Cedars-Sinai Medical Center
Los Angeles
United States
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Sharma, Shilpa; Mehta, Puja K; Arsanjani, Reza et al. (2018) False-positive stress testing: Does endothelial vascular dysfunction contribute to ST-segment depression in women? A pilot study. Clin Cardiol 41:1044-1048
Shufelt, Chrisandra; Manson, Joann (2018) Managing Menopause by Combining Evidence With Clinical Judgment. Clin Obstet Gynecol 61:470-479
Speier, William; Dzubur, Eldin; Zide, Mary et al. (2018) Evaluating utility and compliance in a patient-based eHealth study using continuous-time heart rate and activity trackers. J Am Med Inform Assoc 25:1386-1391
Shufelt, Chrisandra; Bairey Merz, C Noel; Pettinger, Mary B et al. (2018) Estrogen-alone therapy and invasive breast cancer incidence by dose, formulation, and route of delivery: findings from the WHI observational study. Menopause 25:985-991
Shufelt, Chrisandra L; Torbati, Tina; Dutra, Erika (2017) Hypothalamic Amenorrhea and the Long-Term Health Consequences. Semin Reprod Med 35:256-262
Eastwood, Jo-Ann; Taylor, Doris A; Johnson, B Delia et al. (2017) Premature atherosclerosis in premenopausal women: Does cytokine balance play a role? Med Hypotheses 109:38-41