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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.

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.

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.

PURPOSE Bone metastases (BM) occur in approximately 30% of patients with metastatic renal cell carcinoma (mRCC) and are associated with poor survival and symptomatic skeletal events (SSEs). Radium-223, an alpha-emitting bone-seeking radioisotope, and cabozantinib, a tyrosine kinase inhibitor, have demonstrated activity in BM. RADICAL (Alliance A031801; ClinicalTrials.gov identifier: NCT04071223 ) evaluated cabozantinib ± radium-223 in mRCC with BM. METHODS This phase II trial enrolled patients with mRCC of any histology with ≥1 BM. Patients were randomly assigned 1:1 to cabozantinib ± radium-223, stratified by osteoclast-targeted therapy (OTT), prior therapy, opioid use, and International mRCC Database Consortium (IMDC) risk. The primary end point was SSE-free survival (SSE-FS). Secondary end points included safety, objective response rate (ORR), progression-free survival, and overall survival (OS). A target of 124 evaluable patients was planned, with a prespecified interim futility analysis at 50% of expected SSE-FS events; the trial would stop if the stratified hazard ratio (sHR) > 1.0. RESULTS The prespecified interim futility analysis was conducted after 90 patients were enrolled and crossed the futility boundary, leading to closure at 98 patients. The final analysis included all 98 patients. Median age was 63 years, 82.7% had clear cell histology, and 79.6% were using an OTT. IMDC risk was favorable (18.4%), intermediate (67.3%), and poor (14.3%). Median follow-up was 13.1 months. Median SSE-FS for cabozantinib with radium-223 versus cabozantinib was 16.7 versus 17.6 months (sHR, 1.46 [90% CI, 0.86 to 2.51]). Median OS was 28.3 versus 19.7 months (sHR, 1.40 [95% CI, 0.70 to 2.79]). ORR was 19.4% versus 25.0% ( P = .78). Grade ≥3 adverse events were similar across arms (69.6% v 75.5%). CONCLUSION Radium-223 did not improve SSE-FS when added to cabozantinib. The combination demonstrated a manageable safety profile.

Background Mild cognitive impairment (MCI) represents a critical window for both pharmacological therapies and non-pharmacological interventions to delay cognitive decline. Objective To evaluate whether combining pharmacotherapy with multicomponent behavioral interventions enhances outcomes relative to behavioral interventions alone. Methods The sample included people with MCI (pwMCI) of any etiology who completed the HABIT Healthy Action to Benefit Independence & Thinking ® program. Baseline pharmacotherapy (acetylcholinesterase inhibitor and/or glutamate regulators) use was dichotomized (yes/no). Multivariate linear mixed-effects models examined changes from baseline in care partner-reported everyday functional skills, quality of life, self-efficacy, anxiety, depression, and HABIT compliance at post-intervention, 6 months, and 12 months, adjusting for baseline cognitive impairment severity and relevant demographic covariates. Results Among 1074 pwMCI, 413 (38.5%) were receiving pharmacotherapy at baseline. Pharmacotherapy use was more prevalent among White than non-White participants (39.4% versus 23.3%, p = 0.01). At baseline, pharmacotherapy users had more severe cognitive impairment and lower utilization of rehabilitation strategies (all p < 0.05). Both groups demonstrated significant improvements across all outcomes at post-intervention. During follow-up (mean score change compared to baseline), pharmacotherapy users showed greater increases in HABIT compliance at 6 months (3.2 versus 2.0) and 12 months (2.1 versus 1.4). In contrast, by 12 months, pharmacotherapy users experienced greater worsening of everyday functional skills related to memory (−2.1 versus −1.3) and executive function (−5.8 versus-3.7). Conclusions pwMCI undergoing pharmacotherapy entered the HABIT program with more advanced cognitive impairment. The pharmacotherapy was not associated with greater intervention-related benefit or attenuation of long-term cognitive decline.

Objectives Long-term symptoms following infection with acute respiratory syndrome coronavirus-2 (SARS-CoV-2), termed post-acute sequelae of SARS-CoV-2 infection (PASC) or Long COVID (LC), persist beyond 90 days and may impact at least 10% of patients with acute infection. The exact cause of LC remains unknown, but several theories include persistent viral particles, immune dysfunction, and autonomic nervous system (ANS) imbalance, particularly involving the vagus nerve. Given the role of the vagus nerve in inflammation regulation, vagal nerve stimulation (VNS) is being explored as a treatment option. The present study aimed to evaluate the feasibility, safety, and exploratory effects of a handheld external transcutaneous cervical non-invasive VNS (tcVNS) on the primary endpoint of Post-COVID Functional Status (PCFS) grade, alongside secondary outcomes such as LC-related fatigue and other symptoms. Methods Participants from our Post COVID Care Clinic were randomized into treatment (tcVNS treatments two minutes, three times a day) and control (no VNS) groups for a study period of 12 weeks. Participants completed validated questionnaires, PET-CT scans, and inflammatory cytokines at baseline and 12 weeks. Results All randomized patients (8 tcVNS, 10 control) completed the 12-week study. Participants randomized to tcVNS were observed to have improvements in PHQ-9, PROMIS-F, and COMPASS-31 when compared to controls, but these differences were not statistically significant. Cortisol and DHEA were also observed to increase less in the tcVNS group when compared to the control group, but these changes were also not statistically significant. Conclusions tcVNS was well tolerated and may be a promising therapeutic approach for LC, a chronic disease with no approved treatments and very low rates of complete recovery.

BACKGROUND: Primary aldosteronism (PA) is a common and treatable cause of hypertension, yet data on the durability of medical treatment response beyond the first year are limited. Using the PA medical treatment outcomes framework, we evaluated long-term biochemical and clinical outcomes and factors associated with treatment response. METHODS: We conducted an international, multicenter, observational cohort study across 27 centers on 4 continents. Adults with PA treated with mineralocorticoid receptor antagonists and/or epithelial sodium channel blockers between 2016 and 2021 were included if follow-up data were available at ≥12 months. Biochemical and clinical responses were classified as complete, partial, or absent using PA medical treatment outcomes criteria. Ordinal logistic regression identified determinants of a favorable treatment response. RESULTS: The cohort included 1292 patients (47.5% women, mean age 52 years) with a median follow-up of 34 months (interquartile range, 21–51). At ≥12 months, 58.3% achieved a complete biochemical response, and 20.8% achieved a complete clinical response, with only 5% showing no response. Determinants of a favorable biochemical response included lower aldosterone and lateralization index, and higher renin and potassium levels at baseline. In those taking spironolactone, a higher daily dose was also associated with a favorable biochemical response. Determinants of a favorable clinical response included female sex, lower body mass index, shorter duration of hypertension, and absence of hypertension-mediated organ damage. CONCLUSIONS: Targeted medical therapy for PA can deliver sustained biochemical and clinical benefits. Early disease detection and adequate dose titration are highly actionable determinants of long-term treatment success.

Objective: To determine whether normothermic machine perfusion (NMP) mitigates the historical survival disadvantage of donation after circulatory death (DCD) liver transplantation compared with donation after brain death (DBD) livers. Summary Background Data: NMP has improved outcomes in DCD LT compared with static cold storage (SCS), but whether it eliminates the historical disparity relative to DBD transplantation remains uncertain. Methods: We performed a retrospective cohort study of adult LT at a high-volume US center between 2019 and 2024. Outcomes of DCD-NMP grafts were compared with DCD-SCS, DBD-SCS, and DBD-NMP grafts. Primary outcomes were 1-year graft and patient survival. Secondary outcomes included early allograft dysfunction (EAD), hepatic artery thrombosis (HAT), primary nonfunction (PNF), biliary anastomotic strictures (BAS), and ischemic cholangiopathy (IC). Results: Among 1338 liver transplants (DBD-SCS n=527; DBD-NMP n=142; DCD-SCS n=255; DCD-NMP n=414), DCD-NMP grafts had a significantly higher donor risk profile ( P <0.001) yet demonstrated survival comparable to DBD transplantation. One-year graft survival was 94% for DCD-NMP versus 93% for DBD grafts and 86% for DCD-SCS, and 1-year patient survival was 98% for DCD-NMP versus 94% to 95% for DBD grafts and 93% for DCD-SCS. In adjusted models, DCD-SCS was associated with increased hazards of graft loss (adjusted hazard ratio: 2.48; P <0.001) and death (adjusted hazard ratio: 2.39; P =0.004), whereas DBD groups did not differ from DCD-NMP. Incidence of EAD was lower with DCD-NMP (21.7%) than DCD-SCS (50.2%) and similar to DBD grafts (21.1%–26.4%); HAT and PNF were rare (≤1.3%). At 1 year, BAS occurred in 36% of DCD grafts versus 17% to 23% of DBD grafts. IC occurred in 7.7% of DCD-NMP compared with 22% of DCD-SCS and ≤1.5% of DBD grafts. Retransplantation due to IC was infrequent overall (1.3%), but more common in DCD-SCS (4.7%) than DCD-NMP (1.0%) and DBD grafts (≤0.4%). Conclusions: NMP enables safe utilization of DCD liver allografts and achieves graft and patient survival comparable to DBD LT, mitigating the historical disadvantage of DCD grafts. These findings support routine integration of NMP into clinical practice and efforts to standardize its implementation.