Shufelt, Chrisandra L

Objectives: Psychological health changes are known to occur during perimenopause, but the extent to which these differ from premenopause remains unclear. This study aimed to assess psychological symptoms during perimenopause compared with premenopause and evaluate differences by country. Methods: Flo app users aged 35 years or above not taking hormonal contraception or hormone therapy were included. The psychological domain of the Menopause Rating Scale (range 0-16) and symptoms within this domain of depressive mood, irritability, anxiety, and exhaustion (range 0-4 each) were evaluated. Participants in perimenopause were compared with those in premenopause (self-reported not in perimenopause or postmenopause). Results: A total of 7,975 women were included, with 2,353 in perimenopause (mean age 45 years [SD±4.5]) and 5,622 in premenopause (39 y [SD±4.0]). Psychological Menopause Rating Scale scores in the perimenopause group were significantly higher (7.3 [SD±3.56]) than in the premenopause group (4.8 [SD±3.56]; P <0.001). The individual symptoms of depressive mood, irritability, anxiety, and exhaustion were also higher in the perimenopause group ( P <0.001, for all respectively), with the largest difference being exhaustion. These findings remained after adjusting for known confounders, including an existing diagnosis of anxiety or depression. Geographic analysis included 20 countries across 6 continents, with significant differences identified between countries for the overall psychological symptom domain score and all individual symptoms. Conclusion: Significantly greater psychological symptom burden was identified in the perimenopause group compared with the premenopause group, with the greatest difference noted for the individual symptom of exhaustion. Differences in symptom burden were also identified by country.

Objective: Perimenopause is an under-recognized life stage that is often accompanied by complex and fluctuating symptoms. We aimed to quantify the prevalence of perimenopause uncertainty and explore the underlying drivers. Methods: We conducted a mixed-methods study using a cross-sectional survey of US women aged 35 years and above (N=7,640). We estimated the prevalence of perimenopause uncertainty and examined subgroup differences by age and symptom severity. Content analysis of free-text responses (n=409) identified key uncertainty drivers. Results: Overall, 34% (95% CI: 33%-35%) of participants reported being unsure of their reproductive stage. Uncertainty varied by age and symptom severity ( P < 0.001), peaking at 42% (95% CI: 41%-43%) among those aged 40-44 and 37% (95% CI: 36%-38%) among those with severe symptom burden. Content analysis revealed three main uncertainty drivers. Symptom confusion and attribution were the most common (56%), reflecting difficulties interpreting bodily changes and distinguishing perimenopause from other causes. Knowledge gaps and information seeking accounted for 28% of responses, highlighting limited health literacy, age-based assumptions, and active searches for evidence. Barriers to confirmation and care (16%) described dismissive health care encounters and reluctance to acknowledge perimenopause. Younger women (35-39 y) were more likely to cite knowledge gaps, while health care barriers peaked in the 40-44 age group ( P = 0.05). Conclusion: Perimenopause uncertainty is a prevalent and clinically meaningful phenomenon. Conceptually distinct from illness-focused uncertainty, this universal transition frequently involves ambiguity and limited validation. Clarifying symptom patterns, addressing knowledge gaps, and reducing barriers to confirmation may support women during perimenopause.

ABSTRACT Objective This study assessed the impact of sex and age on weight loss outcomes in patients receiving tirzepatide in real‐world clinical practice. Methods We conducted a retrospective cohort study of adults with overweight or obesity who initiated tirzepatide at Mayo Clinic between June 2022 and May 2024 and completed ≥ 12 months of continuous therapy. Primary outcome was total body weight loss percentage (TBWL%) at 15 months, stratified by sex and age groups (≤ 45, 46–59, ≥ 60 years). Results Among 1039 patients (57% women; mean age 56 ± 11 years), women achieved significantly greater TBWL% than men after 15 months of treatment (15.1% vs. 10.7%, p < 0.001). Patients aged ≤ 45 years had greater weight loss than those ≥ 60 years (15.1% vs. 12.3%, p = 0.024). In multivariable analyses, greater weight loss was independently associated with female sex, absence of type 2 diabetes, no prior obesity medication use, no concomitant weight gain‐promoting medications, and higher tirzepatide dosage. Age was not an independent predictor. Conclusions Sex, but not age, predicted weight loss with tirzepatide among individuals using the medication continuously for ≥ 12 months. These findings underscore the importance of incorporating sex‐specific considerations into personalized obesity treatment strategies.

Introduction To assess and compare the accuracy, readability, and overall performance of large language models (LLMs) in answering questions about functional hypothalamic amenorrhea (FHA) for patients and healthcare professionals. Methods A total of 11 patient-level and 15 clinician-level FHA-related questions were entered separately into four LLMs: ChatGPT 3.5 (free version), ChatGPT 4.0 (updated, paid subscription), Gemini, and OpenEvidence. OpenEvidence was used only for clinician-based questions. Responses were evaluated by three expert reviewers blinded to the LLM used who rated them as accurate and complete, accurate but incomplete, or inaccurate. A fourth reviewer resolved discordant scores. Readability for patient-level questions was assessed using the Flesch Reading Ease Score (FRES) and word count. Lower FRES scores indicate more difficult reading. Accuracy and completeness were compared using odds ratios (95% CI) with ChatGPT 3.5 as the reference model, and differences in readability were analyzed using Friedman’s test. Results LLM performance varied across question types. For patient-level questions, ChatGPT 4.0 achieved the highest accuracy (9 of 11; 82%), followed by ChatGPT 3.5 and Gemini (each 8 of 11; 73%), with no statistically significant differences. Among clinician-level questions, OpenEvidence demonstrated perfect accuracy (15 of 15; 100%), compared with 93% for and 80% for ChatGPT 4.0 and Gemini. Completeness followed similar patterns, with OpenEvidence providing the most complete clinician responses (93%) and ChatGPT 4.0 the most complete patient-level responses (89%). Readability differed significantly among models ( p = 0.012), with Gemini producing the most readable patient-level content (median FRES 43.5 [IQR 36.8–53.4]) compared with ChatGPT 3.5 (30.6 [16.8–48.4]) and ChatGPT 4.0 (28.8 [22.1–37.6]). Word counts did not differ significantly ( p = 0.39). Discussion LLMs demonstrated good overall performance in answering FHA-related questions but often provided incorrect or incomplete information. Fine tuning field-specific data, engineered prompts, and obtaining human-in-the-loop feedback may help improve the accuracy of these models.

Abstract Background Wide-spread mast cell (MC)-associated symptoms and MC activation syndrome (MCAS) are often reported in patients with hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD). The goal of this study was to develop a novel MC score based on 11 self-reported MC-related conditions with clinical and research utility to better understand MC symptoms in hEDS and HSD patients. Methods From November 1, 2019, to June 13, 2025, patients ( n =2,141) filled out an Intake Questionnaire at the Mayo Clinic Florida EDS Clinic that included 11 self-reported questions related to categories of MC-related conditions for a MC score ranging from 0/11 to 11/11. Based on the MC score distribution in hEDS and HSD patients, a MC score of 0-1 was considered a low MC score and ≥5 was considered a high MC score. Symptoms/comorbidities were compared between patients with high vs. low MC scores. Results From the 2,141 hEDS/HSD patients, 535 (25.0%) had a MC score ≥5 (Hi MC). MCAS-specific symptoms such as nausea and vomiting were reported more often in hEDS/HSD patients with a high vs. low MC score ( p <0.0001). Random clinical blood tryptase and urinary MC markers were not elevated in patients with high MC scores ( n =50/group), although high MC scores were found to significantly reduce urinary creatinine levels indicating that the protein used to normalize data was affected by MC activity. In contrast, random blood IgE, tryptase and major basic protein (MBP) by ELISA were increased in patients with high MC scores (e.g., IgE hEDS p =0.0004, HSD p =0.003). Of note, the percentage of patients reporting abuse or post-traumatic stress disorder was nearly doubled in patients with high vs. low MC scores (Abuse and PTSD: hEDS p < 0.0001; HSD p < 0.0001). Overall, 109/135 (80.7%) in hEDS and 129/135 (95.6%) in HSD reported more symptoms/comorbidities if they had a high MC score. Conclusions We found that hEDS/HSD patients with high MC scores self-reported more widespread symptoms/comorbidities and higher MC-related blood markers than patients with low MC scores indicating the utility of this tool to evaluate the level of widespread MC activity in hEDS, HSD and other patients.

Importance and Objective: Aging is a complex biological process uniquely shaped in women by hormonal transitions, particularly across the menopause transition. While chronological age alone fails to capture individual health variability, emerging molecular biomarkers offer tools to quantify biological aging and understand mechanisms underlying age-related decline. This review synthesizes the current landscape of aging biomarkers, including senescence-associated secretory phenotype factors, epigenetic clocks, clonal hematopoiesis of indeterminate potential, and telomere length, with a particular emphasis on their relevance to menopause. Methods: This narrative review synthesizes human studies, translational research, and foundational basic science identified through PubMed searches through June 2025, examining aging biomarkers in general populations, among women in the menopause transition, and in relation to vasomotor symptoms and hormone therapy. Discussion and Conclusion: Evidence demonstrates that changes in biological aging biomarkers are observed across multiple molecular systems during midlife, including the menopause transition, reflecting broader age-related biological remodeling. Postmenopausal status, particularly following early or surgical menopause, has been associated with biological aging phenotypes, including elevated senescence-associated secretory phenotype factors, epigenetic age acceleration, clonal hematopoiesis, and shorter leukocyte telomere length, likely reflecting a combination of chronological aging, hormonal changes, and individual biological vulnerability. While severe vasomotor symptoms have been linked to higher epigenetic age, hormone therapy may favorably influence certain senescence markers and biological age discrepancy. Despite these advances, significant limitations constrain clinical translation, as current biomarkers capture overlapping biological processes and lack validated thresholds to define biological aging, especially in women. Future research requires large, longitudinal studies across diverse populations to establish clinically meaningful thresholds and sex-specific calibration. Advancing precision health strategies for women requires a better understanding of how reproductive and hormonal factors modify biomarker trajectories to improve risk prediction and to facilitate the development of targeted interventions for age-related diseases.

Background: Functional hypothalamic amenorrhea (FHA) is a common form of secondary amenorrhea caused partly by undernutrition relative to demand. Objective: To compare the dietary nutritional intake between women with FHA and eumenorrheic controls and evaluate micronutrient profiles. Methods: This cross-sectional study included 30 women with FHA and 29 eumenorrheic controls not on hormones. FHA was defined as ≥3 consecutive months of amenorrhea, estradiol of <50 pg/mL, and FSH and LH of <10 mIU/L, excluding other etiologies. A 3-day food diary was collected for dietary analysis, excluding dietary supplements using ESHA Research Food Processor. Results: The mean age of women with FHA and controls was 26.4 years ± 6.2 versus 30.3 years ± 3.7 ( p = 0.002), with no differences in BMI ( p = 0.16) or the waist-to-hip ratio ( p = 0.71). Women with FHA and controls consumed comparable median calorie intake (1784 kcal [1465, 2011] vs. 1732 kcal [1578, 1982], p = 0.62), with no differences in self-reported exercise patterns. Women with FHA consumed more dietary protein (84.2g [74, 112] vs. 74 g [59, 92], p = 0.001) and dietary fiber (30.1 g [22, 43] vs. 17.3 g [15, 23], p = 0.02) versus controls, respectively. When expressed as a percentage of estimated average requirements (% estimated average requirement), women with FHA had higher intakes of vitamin A (105% [45, 219] vs. 43% [21, 86], p = 0.005), vitamin C (201% [139, 351] vs. 107% [75, 190], p = 0.004), and iron (169% [146, 220] vs. 120% [99, 192], p = 0.027) compared with controls. Conclusions: Women with FHA had similar caloric intake to eumenorrheic controls but consumed more dietary protein, fiber, vitamin A, vitamin C, and iron. Future studies should examine the nutritional profiles of women with FHA in relation to long-term health consequences such as bone and vascular health.

PURPOSE This national study was undertaken to determine screening mammography rates among transgender and gender diverse (TGD) individuals. METHODS TGD individuals and cisgender women who qualified to receive screening mammography based on American College of Radiology guidelines were identified in the longitudinal OptumLabs Data Warehouse. The primary end point was the percentage of patients who had high rates of screening (>75% recommended screenings). Multivariable analyses were conducted in a matched population of transgender men to cisgender women to identify and adjust for factors associated with high adherence. Individuals were matched at a 1:4 ratio (transgender men: cisgender women) on age, race/ethnicity, year of enrollment in their health care plan, and duration of follow-up. RESULTS This study focused on 10,478 TGD individuals (3,778 transgender men; 1,294 transgender women; 5,406 with gender dysphoria not meeting other TGD criteria, NMOT) and 6,218,369 cisgender women. For transgender men, transgender women, individuals with gender dysphoria NMOT, and cisgender women, high mammography rates were observed in 41.1% (95% CI, 39.5 to 42.6), 7.4% (95% CI, 6.0 to 8.8), 11.9% (95% CI, 11.0 to 12.7), and 38.3% (95% CI, 38.3 to 38.4), respectively ( P < .0001). When transgender men were compared with 15,112 matched cisgender women, an age-based differential association was observed between sex and high mammography rates (interaction P = .0003); compared with cisgender women, transgender men appeared more likely to manifest high rates of screening at age 40-49 years (odds ratios [ORs], 1.38 [95% CI, 1.28 to 1.50]; P < .0001) and 50-59 years (OR, 1.57 [95% CI, 1.35 to 1.81]; P < .0001) but not in the older age groups. CONCLUSION The relatively high rates of screening mammography in cisgender women and transgender men suggest clinicians are offering mammography to individuals who are at average or high breast cancer risk, as compared with cisgender women, and not to transgender women at low risk.