THURSDAY CONCURRENT SESSION #1 at baseline, week 12 and months 6, 9 and 12. Changes from baseline to month 12 in lipid and coagulation parameters, blood glucose, and cardiovascular events are summarized descriptively. Results: 1835 women were randomized and took ≥1 capsule of daily S-1. E2/P4 (mg/mg) of 1/100 (n=415), 0.5/100 (n=424), 0.5/50 (n=421), 0.25/50 (n=424) or Effects of Hormone Therapy on Heart Fat and Atherosclerosis placebo (n=151). Total cholesterol and LDL-cholesterol levels numerically decreased Progression in Recently Postmenopausal Women from KEEPS Trial from baseline to month 12, HDL-cholesterol levels remained similar to baseline and Samar R. El Khoudary, PhD, MPH1, Qian Zhao1, JoAnn E. Manson2, Maria M. Brooks1, triglycerides levels increased (Table). Few women had triglycerides and cholesterol Nanette Santoro3, Dennis M. Black4, Mitchell Harman7, Marcelle I. Cedars4, Paul N. increases (≥50 mg/dL or above normal levels) at 12 months with TX-001HR (6-11% and Hopkins8, Ann E. Kearns6, Virginia Miller6, Hugh S. Taylor9, Matthew J. Budoff5. 1-4%, respectively) vs placebo (7% and 3%). Fasting glucose levels remained similar 1University of Pittsburgh, Pittsburgh, PA; 2Harvard Medical School and Brigham and to baseline at 12 months. Antithrombin activity and factor XIV and protein S levels Women’s Hospital, Boston, MA; 3University of Colorado, Aurora, CO; 4University tended to decrease from baseline compared with placebo, and time for activated partial of California San Francisco, San Francisco, CA; 5Los Angeles Biomedical Research thromboplastin, prothrombin time, fibrinogen levels and prothrombin international Institute, Torrance, CA; 6Mayo Clinic, Rochester, MN; 7Phoenix Veterans Affairs normalized ratio remained similar to baseline at 12 months. Two women experienced Health Care System, Phoenix, AZ; 8University of Utah Health, Salt Lake City, UT; “coronary heart disease” adverse events considered not related to treatment: unstable 9Yale University, New Haven, CT angina in one subject (E2/P4 0.5/50), and angina and coronary artery disease in Objective: Heart fat depots, within [epicardial adipose tissue (EAT)] and outside another (E2/P4 1/100). The woman who experienced unstable angina also experienced [paracardial adipose tissue (PAT)] the pericardium, have been linked to increased subarachnoid hemorrhage and cerebellar infarction, neither considered treatment related. cardiovascular disease risk. Postmenopausal women have greater volumes of heart fat One case of deep vein thrombosis (DVT) with E2/P4 0.5/50 was reported in a woman than premenopausal women. Recent evidence suggests a role of endogenous estrogen with a family history of DVT. Conclusion: Twelve months of TX-001HR treatment in in heart fat accumulation, possibly limited to PAT. The impact of hormone therapy menopausal women with VMS and an intact uterus had minimal clinically meaningful (HT) on heart fat buildup is unknown. We evaluated the differential effects of HT effects on lipid, glucose, or coagulation parameters. Observed changes in triglyceride on the accumulation of heart fat depots and their associations with coronary artery levels, antithrombin activity, factor XIV, and protein S were consistent with oral estrogen calcification (CAC) progression in recently postmenopausal women. Design: KEEPS therapy. Although this trial lacked statistical power to assess these outcomes, VTE rates, was a multi-center, randomized, clinical trial of the effects of oral conjugated equine cardiovascular disease, and cerebrovascular events were as expected for a postmenopausal estrogens (o-CEE) and transdermal 17β-estradiol (t-E2), both with progesterone, population. If approved, TX-001HR may provide the first oral combination of E2/P4 for compared to placebo, on 48-month subclinical atherosclerosis progression in recently the treatment of VMS in menopausal women with a uterus. postmenopausal women. Heart fat volumes and CAC were measured on CT scans at Sources of Funding: TherapeuticsMD baseline and 48 months later. Significant CAC progression was defined as present if (1) baseline CAC score = 0 and 48 month CAC Agatston score >0 ; (2) baseline CAC score >0 to <100 and annualized change in CAC score ≥10 ; or (3) baseline CAC score ≥100 and annualized percent change in CAC score ≥10%. Changes in heart fat depots were tested using Wilcoxon signed test and compared by treatment group using Kruskal– Wallis test. Associations between change in heart fat volumes and CAC progression as well as effect modification by HT type were tested using logistic regression adjusting for age, race, study site, education, physical activity, smoking, alcohol intake, lipids, systolic blood pressure, waist circumference, anti-hypertensive medications and baseline heart fat volume. Results: Of 727 randomly assigned women, 474 [mean age (SD): 52.7(2.6); 78.1% White] had heart fat volumes and CAC scores at baseline and 48 months. EAT volume increased significantly over time in the placebo group [median (Q1, Q3): 2.12(-4.58, 6.36) cm3, P=0.003] but not in the o-CEE [-0.05(-5.93, 6.12) cm3, P>0.99] or the t-E2 group [1.68(-4.07, 4.91) cm3, P=0.07]. PAT volume did not change significantly in any group. Changes in EAT and PAT did not vary by treatment group. KEEPS only included women whose screening CAC score was < 50, resulting in 88.4% of participants having CAC=0 at baseline. At 48 month CAC progressed in 14% of the study participants. Changes in EAT and PAT were not significantly associated with CAC progression overall. However, assigned treatment significantly modified the association between changes in PAT and CAC progression in adjusted model, P=0.02, such that changes in PAT were associated with greater CAC progression risk only in t-E2 group [OR (95% CI) per 1 SD of PAT change: 2.8(1.3, 5.9)]. Conclusion: There was no significant difference among treatment groups in 48 month changes of heart fat depots. However, there was a suggestion that O-CEE slowed progress on heart fat accumulation, although not in the t-E2 group. Greater PAT changes were associated with greater CAC progression risk only in the t-E2 group. The current findings support the notion that EAT and PAT are distinct fat depots and suggest a complex role of HT in the accumulation of heart fat depots and their associations with CAC progression in recently postmenopausal women. Sources of Funding: KEEPS: Aurora Foundation to the Kronos Longevity Research Institute, NIH P50 AG 44170 to VMM, 1 UL1 RR024150, Mayo CTSA 1 UL1 RR024150, the Mayo Foundation, CTSA UL1 RR024139, UL1 RR024131 from the NCRR. Study medications: supplied in part by Bayer Health Care and by Abbott aPTT: activated partial thromboplastin time; INR: international normalized Pharmaceuticals. The ClinicalTrials.gov number is NCT00154180. KEEPS Heart Fat ratio. Ancillary study: NHLBI R21HL140011. S-3. S-2. Evaluation of Systemic Effects of a Vaginal Estradiol Softgel Capsule Effects of Single-Capsule 17β-Estradiol/Progesterone (TX-001HR) on (TX-004HR) in Menopausal Women with Moderate-to-Severe Dyspareunia Metabolic Parameters and Cardiovascular Outcomes in Menopausal Lisa C. Larkin MD, MD5, Andrew M. Kaunitz, MD1, James Liu, MD2, Shelli Graham, Women of the REPLENISH Trial PhD3, Brian Bernick, MD3, Sebastian Mirkin, MD3, Ginger Constantine4. 1University Rogerio Lobo, MD1, James Liu, MD2, Andrew M. Kaunitz, MD3, Brian Bernick, MD4, of Florida College of Medicine-Jacksonville, Jacksonville, FL; 2University Hospitals Shelli Graham, PhD4, Ginger Constantine5, Sebastian Mirkin, MD4. 1Columbia University Cleveland Medical Center, Cleveland, OH; 3TherapeuticsMD, Boca Raton, FL; Medical Center, New York, NY; 2University Hospital Cleveland Medical Center, 4EndoRheum Consultants, LLC, Malvern, PA; 5Lisa Larkin MD and Associates, Cleveland, OH; 3University of Florida College of Medicine-Jacksonville, Jacksonville, Mariemont, OH FL; 4TherapeuticsMD, Boca Raton, FL; 5EndoRheum Consultants, LLC, Malvern, PA Objective: TX-004HR (an investigational, vaginal softgel capsule of low-dose, Objective: TX-001HR (TherapeuticsMD, Boca Raton, FL), an investigational product solubilized 17β-estradiol, designed to be mucoadhesive and rapidly dissolving) that combines 17β-estradiol and progesterone (E2/P4) in a single, oral softgel capsule, significantly improved vaginal physiology and dyspareunia (primary endpoints) as well as significantly reduced the frequency and severity of moderate-to-severe vasomotor dryness (secondary enpoint) in menopausal women with moderate-to-severe dyspareunia symptoms (VMS) in menopausal women of the REPLENISH trial (Lobo et al, Obstet as their most bothersome symptom in the phase 3 REJOICE trial (NCT02253173).1 Gynecol 2018, in press). The objective of this report is to summarize safety endpoints Improvements were achieved with negligible to very low systemic absorption of related to metabolic parameters and cardiovascular outcomes from REPLENISH. estradiol with doses of 4 µg, 10 µg and 25 µg (the 4 µg and 10 µg doses have been Design: REPLENISH (NCT01942668) was a phase 3, randomized, double-blind, submitted for FDA approval).2 Systemic levels of estradiol with 10 µg and 25 µg doses placebo-controlled, multicenter trial that evaluated 4 TX-001HR doses vs placebo in were shown to be lower than with the same doses of a commercially available vaginal menopausal women (40-65 years) with a uterus. Women were randomized to E2/P4 estradiol tablet (Vagifem®) in head-to-head studies.3 This report summarizes the effects doses or placebo in a proportion