Shufelt, Chrisandra

Abstract Disclosure: E. Tama: None. R. Rivera: None. S. Fansa: None. D. Anazco: None. W. Ghusn: None. S. Faubion: None. A. Acosta: Consulting Fee; Self; Amgen Inc. Grant Recipient; Self; Vivus USA, Novo Nordisk. C. Shufelt: None. M.D. Hurtado: None. Introduction: Midlife women (ages 40 to 65) experience age-related weight gain (0.4-0.7 kg/year) due to physiologic and psychosocial changes. Evidence supports that age-related decrease in lean mass and its subsequent effect on energy expenditure are key physiologic factors. To date, the are no data describing if changes in the main regulators of energy intake (i.e., hunger, satiation, and satiety) across women’s lifespan play a role in weight gain during midlife. The aim of this study is to characterize measurements of satiation, satiety, and appetite sensations through early adulthood and midlife in women with obesity. Methods: This is a cross sectional study of women aged 19-65 with overweight or obesity who have undergone measurements of (i) body composition by DXA scan; (ii) resting energy expenditure (REE) by indirect calorimetry; (iii) satiation by calories consumed to satiation (CTS) during an ad libitum meal test; (iv) satiety by time needed to empty 50% of the stomach content (GEt1/2) in a gastric emptying study and plasma satiety hormone levels (PYY, GLP-1, and CCK); and (v) appetite sensations by visual analog scales (VAS) for hunger and fullness. We present data as mean ± standard deviation. We performed simple correlations between these variables and age. We performed multiple regression analyses to adjust for body composition and REE. Results: Our cohort included 552 mostly white (93%) women, with a mean age of 41±11 years and a mean BMI of 37±7 kg/m2. Increased age significantly correlated with higher waist circumference (r=0.1, p=0.006), waist/hip ratio (r=0.1, p=0.01), and total fat mass % (r=0.1, p=0.04); and with lower lean mass % (r=-0.1, p=0.04) and REE (r=-0.3, p<0.0001). Increased age was associated with decreased hunger sensation (i.e., lower preprandial VAShunger after an overnight fast, r=-0.1, p=0.04; and lower postprandial VAShunger 4hr after a standardized 320-kcal breakfast, r=-0.1, p=0.001), stronger satiation (i.e., lower CTS, r=-0.1, p=0.001), and more prolonged satiety (i.e., higher GEt1/2, r=0.1, p=0.02; higher postprandial GLP-1 levels, r=0.1, p=0.03; and higher postprandial VASfullness after and ad libitum meal, p=0.1, p=0.008). After adjusting for lean mass % and REE, the correlations between age and hunger sensations and satiation measurement, but not satiety measurements, were maintained. Conclusion: Our results show that older women have lower lean mass % and REE. After adjusting for these variables, older women experience decreased hunger sensation and achieve satiation with a lower number of calories. As these changes in theory would protect against midlife weight gain, the differences in body composition and REE remain the most likely culprit. Further research is necessary to investigate if there are other key factors that may contribute to weight gain such as the hedonic or emotional components of food intake. Presentation: 6/2/2024

Abstract Disclosure: E.R. Uddenberg: None. N. Safwan: None. G. Cook-Wiens: None. O. Obrutu: None. M. Saadedine: None. M.D. Hurtado: None. S. Faubion: None. M.D. Pisarska: None. S.L. Berga: None. J.E. Manson: None. C.N. Bairey Merz: None. C.L. Shufelt: None. Background: Functional hypothalamic amenorrhea (FHA) occurs in women of reproductive age and is a common form of secondary amenorrhea that results in hypoestrogenemia and hypercortisolemia. The underlying cause of FHA is due to a mismatch between energetic intake and expenditure that often manifests as disordered eating, excessive exercise, and psychosocial stress. Previous research identified that 1 in 3 women with FHA had endothelial dysfunction, a preclinical marker for cardiovascular disease. We sought to evaluate the nutrition content in young women with FHA compared to eumenorrheic controls and further assess the relationship to endothelial dysfunction. Methods: We enrolled 30 women with FHA and 29 eumenorrheic controls, not on hormones. FHA was defined as ≥3 consecutive months of amenorrhea, estradiol <50 pg/mL, FSH<10 mIU/L, and LH<10 mIU/L, and exclusion of polycystic ovary syndrome, hyperprolactinemia, thyroid dysfunction, and pregnancy. Eumenorrheic controls had monthly menses with ovulation (progesterone ≥4 ng/mL). Vascular function was measured using EndoPAT 2000 (Itamar® Medical Ltd) to calculate the reactive hyperemic index (RHI). An RHI ≤1.67 indicates endothelial dysfunction. Nutritional intake was collected using a 3-day food diary and analyzed using ESHA Research Food Processor® Nutrition Analysis. Percent (%) recommendation values for nutrition content comparison were calculated based on height, weight, and age. Statistical analysis included Analysis of Variance and Kruskal Wallis test with nonparametric variables reported as median [IQR]. Results: The mean age and BMI of FHA and controls were 26.4 ± 6.2 yrs and 30.3 ± 3.7 yrs (p=0.008), and 21.6 ± 6.2 and 21.8 ± 2.0 kg/m2 (p=0.16), respectively. The median months of FHA amenorrhea was 12 months [5.0, 34.0]. After adjusting for age, there was no difference in caloric intakes in women with FHA compared to controls (1783.9 [1465, 2011] kcal vs. 1731.9 [1578, 1982] kcal, p=0.73); however FHA has higher intake of grams of protein (84.2 [74, 112] g vs. 74 [59, 92] g, p=0.0036), and higher grams of dietary fiber (30.1 [22, 43] g vs. 17.3 [15, 23] g, p=0.0037), respectively. In women with FHA, endothelial dysfunction was associated with a higher % recommended calories (p=0.0098), calories from fat (p=0.02), grams of saturated fat (p=0.03), and grams of carbohydrates (p=0.049). Conclusions: Our results demonstrate that women with FHA consumed similar daily calories, although more grams of protein and dietary fiber than controls. In women with FHA, higher calories, calories from fat, grams of saturated fat and carbohydrates were associated with endothelial dysfunction. Future studies should aim to identify other factors related to endothelial dysfunction among women with FHA and whether some FHA phenotypes are associated with more endothelial dysfunction than others. Presentation: 6/1/2024

Abstract Objective To compare weight loss response and changes in cardiometabolic risk markers in postmenopausal women using semaglutide with and without menopause hormone therapy (HT) use. Methods Retrospective cohort study of postmenopausal women treated with semaglutide for overweight or obesity for ≥3 months. Endpoints: total body weight loss percentage (TBWL%) at 3, 6, 9, and 12 months after semaglutide initiation; and percentage of women achieving ≥5% and ≥10% TBWL and changes in cardiometabolic risk markers (glucose, blood pressure, and lipids) at 12 months. Results There were 16 women on HT and 90 on no-HT; mean age 56 ± 8 vs 59 ± 8 yr, P = 0.2 and mean BMI 36 ± 5 vs 39 ± 8 kg/m2, P = 0.1; respectively. Among women on no-HT, White race, dyslipidemia, and depression were more prevalent. Women on HT had a higher TBWL% at 3, 6, 9, and 12 months: 7 ± 3% vs 5 ± 4%, P = 0.01; 13 ± 6% vs 9 ± 5%, P = 0.01; 15 ± 6% vs 10 ± 6%, P = 0.02; and 16 ± 6% vs 12 ± 8%, P = 0.04; respectively. After adjusting for potential confounders, this association remained significant across time. At 12 months, a greater percentage of women on HT achieved ≥5% and ≥10% TBWL. Both groups experienced an improvement in cardiometabolic risk markers. Conclusion In postmenopausal women with overweight or obesity treated with semaglutide, HT use was associated with an improved weight loss response. This association was maintained when adjusted for confounders. Larger studies should be conducted to confirm these results.

Abstract Disclosure: S. Fansa: None. W. Ghusn: None. E. Tama: None. B. Nicolalde: None. D. Anazco: None. S. D'Andre: None. S. Faubion: None. C. Shufelt: None. A. Acosta: None. M.D. Hurtado: None. Background: Aromatase inhibitors (AIs) block estrogen synthesis and are used as adjuvant treatment for breast cancer. AIs are associated with weight gain that can lead to increased cardiometabolic risk, thereby affecting health and survivorship quality in these patients. The role of anti-obesity medications (AOMs) in patients using AIs has not been studied. We sought to investigate weight loss outcomes to AOMs in patients taking AIs for breast cancer treatment. Methods: This is a matched case-control retrospective cohort study of breast cancer survivors on AI using FDA-approved AOMs (AI/AOM group). We compared their weight loss outcomes with a group of female patients with obesity, without a history of breast cancer or AI use, on AOMs (AOM group). We matched patients by age and body mass index (BMI). Exclusion criteria: AOM initiation prior to AI therapy, ≤3 months of AOM use, history of bariatric surgery, active malignancy, or pregnancy. Primary endpoint: total body weight loss % (TBWL%) at 12 months. Secondary endpoints: TBWL% at 3 and 6 months and % of patients achieving categorical TBWL ≥5%, ≥10% and ≥15% at 12 months. We used Pearson χ2 and unpaired t-test to compare baseline characteristics and outcomes between groups, and univariate analyses to estimate the contribution of variables to TBWL% in the AI/AOM group. We present results as mean ± standard deviation. Results: We included 99 patients: 63 in the AI/AOM group (63.5±10 years, BMI 34.4±7.0 kg/m2) and 36 in the AOM group (60.4±8.7 years, BMI 36.3±6.9 kg/m2). Liraglutide, semaglutide and phentermine were the only AOMs used. There was no difference in the frequency of use of these three AOMs among both groups (p= 0.1). AI/AOM group had a lower TBWL% compared to the AOM group during follow-up: 3.7± 4.3% vs. 5.6 ± 4.1% (p= 0.03) at 3 months, 3.9± 4.3% vs. 9.5± 4.7% (p< 0.0001) at 6 months, and 5.2± 5.3% vs. 10.5± 6.8% (p< 0.0001) at 12 months. Although the AI/AOM group was more likely to use lower doses of AOMs (p= 0.0004), TBWL% differences persisted among groups at 12 months after adjusting for AOM dosing (p< 0.0001). There was no difference in nutritional and behavioral modification sessions among groups (p=0.06 and p=0.9, respectively). At 12 months, the percentage of patients achieving ≥5%, ≥10%, and ≥15% TBWL was greater in the AOM group compared to the AI/AOM group: ≥5% TBWL, 85.7% vs. 50.0% (p< 0.0001); ≥10%, 57.1 vs. 20.0% (p< 0.0001); and ≥15%, 28.6 vs. 5.0% (p< 0.0001); respectively. We found no predictors of TBWL% at 12 months in the AI/AOM group. Conclusion: Weight loss outcomes in breast cancer survivors on AIs taking AOMs are poorer compared to patients without breast cancer history and not taking AIs. Studies are needed to assess the mechanisms behind the different weight loss response to AOMs in women taking AIs, which we hypothesize may relate to AIs’ anti-estrogenic effect on lean and fat mass. Presentation: Friday, June 16, 2023

Background: Proprotein convertase subtisilin/kexin 9 (PCSK9) raises low-density lipoprotein cholesterol (LDL-C) levels and is associated with inflammation, which is elevated in HIV and hepatitis C virus (HCV) infection. We compared PCSK9 levels in people with co-occurring HIV and HCV (HIV/HCV) vs. HIV alone, and evaluated the impact of HCV direct-acting antiviral (DAA) therapy on PCSK9. Design: A prospective, observational cohort study. Methods: Thirty-five adults with HIV/HCV and 37 with HIV alone were evaluated, all with HIV virologic suppression and without documented cardiovascular disease. Circulating PCSK9 and inflammatory biomarkers were measured at baseline and following HCV treatment or at week 52 (for HIV alone) and compared using Wilcoxon tests and Spearman correlations. Results: At baseline, PCSK9 trended higher in HIV/HCV vs. HIV alone (307 vs. 284 ng/ml, P = 0.06). Twenty-nine participants with HIV/HCV completed DAA therapy with sustained virologic response. PCSK9 declined from baseline to posttreatment 1 (median 7.3 weeks after end of therapy [EOT]) and posttreatment 2 (median 43.5 weeks after EOT), reaching levels similar to HIV alone; median within-person reduction was -60.5 ng/ml (P = 0.003) and -55.6 ng/ml (P = 0.02), respectively. Decline in PCSK9 correlated with decline in soluble (s)E-selectin and sCD163 (r = 0.64, P = 0.002; r = 0.58, P = 0.008, respectively), but not with changes in LDL-C or other biomarkers. No significant change in PCSK9 occurred in the HIV alone group over 52 weeks. Conclusion: PCSK9 declined with DAA therapy in participants with HIV/HCV, correlating with declines in several inflammatory biomarkers but not LDL-C. Elevated PCSK9 with HCV may be linked to particular HCV-associated inflammatory pathways more so than cholesterol homeostasis.

Abstract Objective Adverse childhood experiences (ACEs) are reported in more than half of the women in the United States and have been shown to negatively impact the menopause experience. The objective of this study was to evaluate the association between ACEs and age at natural menopause. Methods This is a cross-sectional study conducted among participants of the Data Registry on the Experiences of Aging, Menopause, and Sexuality (DREAMS). The registry included women who were seen for consultations in the women's health clinic at Mayo Clinic, Rochester, between May 2015 and December 2016. Only postmenopausal women were included in this analysis. Childhood adversity was assessed with the validated ACE questionnaire. Age at natural menopause was self-reported. The association between ACEs and age at menopause was evaluated using a multivariable linear regression model adjusting for multiple confounders. Results A total of 350 women were evaluated. The mean age was 59.2 years, and a majority were White (92.9%), married/partnered (82%), and educated (91.2% with at least some college education). Women with a history of at least four ACEs were estimated to reach natural menopause 1.3 years sooner than women with no ACE in multivariable analysis, but the results were not statistically significant (95% confidence interval, −3.2 to 0.6; P = 0.18). Conclusions Although stressful life experiences such as ACEs may negatively influence health for midlife women, this study did not find an association with the age at natural menopause.

Abstract Context Endothelial dysfunction is a preclinical cardiovascular disease (CVD) marker. Due to various neuroendocrine aberrations, functional hypothalamic amenorrhea (FHA) may be a sex-specific risk factor for CVD in young women. Objective To investigate endothelial function in women with FHA, compared with eumenorrheic controls and recently menopausal women. Methods We performed a cross-sectional analysis among women with FHA (n = 30), eumenorrheic controls (n = 29), and recently menopausal women (n = 30). FHA was defined as amenorrhea ≥3 consecutive months, estradiol <50 pg/mL, follicle-stimulating hormone (FSH) < 10 mIU/mL, and luteinizing hormone (LH) < 10 mIU/mL, excluding other etiologies. Participants were recruited through obstetrics and gynecology referrals, social media advertising, and review of electronic health records. Preclinical CVD was measured using EndoPAT 2000 to calculate reactive hyperemic index (RHI). RHI ≤1.67 indicates endothelial dysfunction. Results Mean estradiol levels in women with FHA, as compared with eumenorrheic controls and recently menopausal women, were 29.0 ± 18.1, 46.4 ± 15.7, and 10.9 ± 14.4 pg/mL (P < .0001), respectively. Women with FHA had lower insulin (P = .0095) and higher cortisol (P = .0004) compared with controls. RHI was significantly lower in women with FHA compared with eumenorrheic controls and recently menopausal women (1.8 ± 0.5 vs 2.2 ± 0.5 vs 2.2 ± 0.6, respectively; P = .008), and 35% of women with FHA had RHI ≤1.67, consistent with endothelial dysfunction. Conclusion These results demonstrate endothelial dysfunction in 1 out of 3 young women with FHA. FHA may be a contributor to preclinical CVD, and it is not explained by hypoestrogenemia alone.