Hurtado Andrade, Maria D

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.

Importance and Objective: Sexual health is a multidimensional aspect of women’s well-being. It is particularly vulnerable during midlife, when the physiological and psychosocial changes of the menopause transition intersect with the growing burden of obesity. Glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as highly effective pharmacologic treatments for obesity, yet their effects on female sexual function remain largely uncharacterized. This review aims to discuss the interplay among obesity, midlife, obesity treatments, and female sexual health, with a focused synthesis of available evidence on GLP-1–based therapies and sexual outcomes in women. Methods: This narrative review synthesizes preclinical studies, case reports, observational data, and clinical trials identified through PubMed searches from inception through March 2026, examining female sexual function in the context of obesity, the menopause transition, obesity treatments, and GLP-1 receptor agonist therapy. Discussion and Conclusion: Obesity impairs female sexual function through hormonal, vascular, and psychosocial mechanisms. Accordingly, lifestyle interventions and bariatric surgery have demonstrated meaningful improvements in sexual function. In contrast, GLP-1 receptor agonists, despite conferring substantial weight loss and favorable metabolic effects, may paradoxically suppress sexual desire and arousal through central neuroendocrine mechanisms, including the modulation of dopaminergic reward and serotonergic signaling. While emerging case reports and preclinical data support this concern, systematic clinical evidence remains limited, highlighting the need for prospective studies with longitudinal sexual function endpoints. In this context, clinicians should proactively assess sexual function before and during GLP-1 therapy using validated instruments and integrate sexual health into comprehensive obesity care for midlife women.

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.

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.

Objective Increased visceral fat and sarcopenia are cardiovascular risk factors that may explain increased cardiovascular morbidity and frailty in patients with adrenal adenomas. Our objective was to compare body composition measurement of patients with adrenal adenomas to referent subjects without adrenal disease. Design Cross-sectional study, 2014–2018. Methods Participants were adults with nonfunctioning adrenal tumor (NFAT), mild autonomous cortisol secretion (MACS), and Cushing syndrome (CS) and age, sex, and BMI 1:1 matched referent subjects without adrenal disorders. Main outcome measures were body composition measurements calculated from abdominal CT imaging. Intra-abdominal adipose tissue and muscle mass measurements were performed at the third lumbar spine level. Results Of 227 patients with adrenal adenomas, 20 were diagnosed with CS, 76 with MACS, and 131 with NFAT. Median age was 56 years (range: 18–89), and 67% were women. When compared to referent subjects, patients with CS, MACS, and NFAT demonstrated a higher visceral fat (odds ratio (OR): 2.2 (95% CI: 0.9–6.5), 2.0 (1.3–3.2), and 1.8 (1.2–2.7) and a lower skeletal muscle area (OR: 0.01 (95% CI: 0–0.09), 0.31 (0.18–0.49), and 0.3 (1.2–2.7)) respectively. For every 1 µg/dL cortisol increase after overnight dexamethasone, visceral fat/muscle area ratio increased by 2.3 ( P = 0.02) and mean total skeletal muscle area decreased by 2.2 cm 2 ( P = 0.03). Conclusion Patients with adrenal adenomas demonstrate a lower muscle mass and a higher proportion of visceral fat when compared to referent subjects, including patients with NFAT. Even a subtle abnormality in cortisol secretion may impact health of patients with adenomas.

AbstractObjectivesLong-term follow-up is important for determining performance characteristics of thyroid fine-needle aspiration (FNA).MethodsHistologic or 3 or more years of clinical follow-up was used to calculate performance characteristics of thyroid FNA before and after implementation of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). The impact of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) classification was also investigated.ResultsFollow-up was obtained for 1,277/1,134 and 1,616/1,393 aspirates/patients (median clinical follow-up, 9.9 and 4.4 years, pre- and post-TBSRTC, respectively). Nondiagnostic, suspicious for follicular neoplasm, and suspicious for malignancy (SFM) diagnoses decreased and benign diagnoses increased post-TBSRTC, while atypical rate remained less than 1%. Negative predictive value for benign nodules and positive predictive value (PPV) for SFM increased significantly. Eleven nodules were reclassified as NIFTP, slightly decreasing PPV/risk of malignancy (ROM).ConclusionsAppropriate ROM for thyroid FNA can be achieved through application of TBSRTC terminology with minimal use of atypical category.