Safwan, Nancy

Introduction Functional hypothalamic amenorrhea (FHA) accounts for 30% of secondary amenorrhea and is characterized by hypothalamic hypercortisolemia, hypothalamic hypothyroidism, and anovulation with hypoestrogenemia due to disrupted GnRH drive. While FHA is associated with decreased bone mineralization; it remains unclear how bone health compares to menopausal women, who also experience bone loss. This study compared dual-energy x-ray absorptiometry (DXA) bone health parameters among women with FHA, eumenorrheic controls, and recently menopausal women. It also examined the impact of prior combined oral contraceptive (COC) use on bone mineral density (BMD) in women with FHA. Methods This cross-sectional study included 20 women with FHA, 9 eumenorrheic controls, and 12 recently menopausal women who underwent hip and spine DXA. None of the participants were taking hormone therapy. FHA was defined as ≥3 months of amenorrhea, estradiol <50 pg/ml, FSH and LH <10 mIU/L, excluding other etiologies. DXA bone parameters were measured using Lunar iDXA (GE) including BMD from lumbar spine (L1-L4) and hip. Results By design, age differed significantly across groups (p < 0.0001), with median ages of 27.8 years [23.4, 34.1] in women with FHA, 29.6 years [28.3, 32.4] in eumenorrheic controls, and 55.3 years [53.5, 56.6] in recently menopausal women. There were no significant differences in weight or BMI across groups. Significant differences were observed at all measured skeletal sites, including all lumbar spine levels, femur neck, total femur, and total BMD (all p < 0.05). Pairwise comparisons revealed that lumbar spine BMD was significantly lower in FHA compared to eumenorrheic controls (p = 0.04), while FHA and menopausal women did not significantly differ from each other (p = 0.07). Among FHA women with prior COC use, L1–4 BMD was not significantly different from controls (p = 0.19). Conclusions Lumbar spine BMD in young women with FHA was comparable to that of recently menopausal women, highlighting the profound skeletal impact of chronic estrogen deficiency. Prior COC use may partially attenuate FHA-associated bone loss, though larger studies are needed to confirm this observation. Future studies should explore whether skeletal outcomes vary by FHA etiology and the potential role of COC duration in preserving BMD.

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.

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.

Objective: Generative artificial intelligence is rapidly evolving and is now being explored in health care to support patient and clinician education. This study evaluated the accuracy, completeness, and readability of four large language models (LLMs): ChatGPT 3.5, Gemini, ChatGPT 4.0, and OpenEvidence in answering questions about menopause and hormone therapy. Methods: A total of 35 questions (20 patient-level, 15 clinician-level) were entered into each LLM. OpenEvidence was only used for clinician-level questions. Four blinded expert reviewers rated responses as accurate and complete, accurate but incomplete, or inaccurate. Readability of patient-level responses was assessed using the Flesch Reading Ease Score (FRES) and word count. Analysis used ANOVA for readability, odds ratios for accuracy comparisons. Results: For patient-level questions, ChatGPT 3.5 achieved the highest accuracy (70%), followed by ChatGPT 4.0 (60%) and Gemini (30%); Gemini had significantly lower odds of accuracy compared with ChatGPT 3.5 (OR=0.18, 95% CI=0.05-0.71; P =0.014). FRES scores differed significantly ( P <0.001): Gemini scored 38.9±7.3 (“difficult”), ChatGPT 3.5 scored 31.0±11.2, and ChatGPT 4.0 scored 26.5±8.6 (both “very difficult”). For clinician-level questions, ChatGPT 4.0 achieved the highest accuracy (67%), followed by ChatGPT 3.5 and OpenEvidence (60% each) and Gemini (47%); no significant differences were observed among models (all P >0.05). Conclusion: LLMs demonstrated limited accuracy and frequent incorrect or incomplete responses to menopause-related queries, highlighting the need to improve model performance to ensure accurate and reliable information for both patients and clinicians.

Objective: To evaluate the documentation of menopause-related International Classification of Diseases-10 (ICD-10) codes in the electronic health record (EHR) among midlife women with moderate or greater menopause symptoms receiving primary care. Methods: This cross-sectional study from the Hormones and Experiences of Aging (HERA) cohort included women aged 45-60 years receiving primary care at one of 4 Mayo Clinic sites who completed a one-time survey between March 1, 2021 and June 30, 2021. The survey captured demographic data, menopause symptoms using the Menopause Rating Scale (MRS), health care utilization, and treatment. Women with an MRS score ≥12 were included. The primary outcome was documentation of a menopause-related ICD-10 code in the EHR in the 12 months before survey completion. Results: Of 5,254 women with completed surveys, 2,414 (49%) had an MRS score ≥12 and were included. Among these, 1,519 (63%) reported seeking care for their menopause symptoms in the past 12 months, but only 345 (23%) had a menopause-related ICD-10 code. Women with an ICD-10 code had higher MRS scores (18 [IQR: 14-22] vs 17 [IQR: 14-20]; P = 0.002) and were more likely to use systemic hormone therapy (HT; 26% vs 9%; P < 0.001), and vaginal HT (20% vs 6%; P < 0.001). Conclusions: Menopause-related ICD-10 diagnosis codes were under-documented in women with significant menopause symptom burden. Those with a code were more likely to report menopause treatment. These findings highlight a critical gap between symptom burden and diagnosis coding in the EHR, underscoring the need to improve identification and management of menopause symptoms.

Abstract Context Endothelial dysfunction and altered psychological measures have been identified in women with functional hypothalamic amenorrhea (FHA). Estradiol (E2) replacement, a known vasodilator, may potentially reverse vascular dysfunction and improve psychological health. Objective To evaluate 12 weeks of physiologic E2 replacement on vascular, hormonal, and psychological outcomes in women with FHA. Methods A randomized, double-blind, placebo-controlled trial was conducted in 29 women with FHA with 0.1 mg/day transdermal E2 (n = 14) or placebo patch (n = 15) twice weekly for 12 weeks. FHA was defined as amenorrhea ≥3 consecutive months, E2 &lt; 50 pg/mL, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) &lt;10 mIU/L, LH:FSH &lt;1, excluding other etiologies. Endothelial dysfunction (reactive hyperemic index ≤ 1.67) was assessed, as were hormonal and psychological measures. Results Women with FHA had a mean age of 26.2 ± 6.3 years, body mass index of 21.5 ± 3.3 kg/m2, with 63% being non-Hispanic White. Baseline characteristics did not differ between groups. After 12 weeks, E2 levels were significantly higher in the E2 group (112.0 vs 36.5 pg/mL, P = .0002). However, there were no significant differences in vascular, hormonal, or psychological outcomes between E2 and placebo groups at week 12. Cortisol levels showed a near-significant decrease in the E2 group compared to an increase with placebo (−.4 vs 3.1 µg/dL, P = .05). Conclusion In women with FHA, 12 weeks of transdermal E2 increased serum E2 levels but did not improve vascular or psychological health measures. Further studies with larger sample sizes and longer follow-up are needed to explore the long-term effects of E2 therapy on cardiovascular and mental health outcomes in this population.