Journal of Endocrinological Investigation最新文献

{"title":"Validation of the Italian version of the hypoparathyroidism patient questionnaire-28 (HPQ-28): a multicenter study.","authors":"Francesco Arcidiacono, Gianluca Sesso, Antonio Prinzi, Ignazio Barca, Andrea Palermo, Giada Da Re, Anda Mihaela Naciu, Gaia Tabacco, Heide Sigglekow, Francesco Frasca, Pasqualino Malandrino","doi":"10.1007/s40618-026-02944-x","DOIUrl":"10.1007/s40618-026-02944-x","url":null,"abstract":"<p><strong>Purpose: </strong>Hypoparathyroidism (HypoPT) is a rare endocrine disorder frequently associated with impaired quality of life. Disease-specific patient-reported outcome measures may help to better characterize symptom burden in Hypoparathyroid patients. The Hypoparathyroidism Patient Questionnaire-28 (HPQ-28) was originally developed in German and subsequently validated French. The aim of this study was to validate the Italian version of the HPQ-28 in a multicenter cohort.</p><p><strong>Methods: </strong>In this cross-sectional study, adult participants were recruited from two tertiary referral centres in Italy. The study population were divided in three groups: patients with chronic postsurgical HypoPT (Group 1), patients with hypothyroidism without HypoPT (Group 2), and healthy controls (Group 3). Structural validity was assessed using confirmatory factor analysis with a weighted least squares mean- and varianceadjusted estimator. Internal consistency was evaluated using Cronbach's alpha and McDonald's omega coefficients. Test-retest reliability was assessed using intraclass correlation coefficients in a subgroup of patients. Construct validity was examined by comparing HPQ-28 scores across clinical groups.</p><p><strong>Results: </strong>A total of 163 participants were included (69 HypoPT patients, 60 hypothyroid patients, and 34 controls). Confirmatory factor analysis supported the original six-factor structure of the HPQ-28, with acceptable goodness-of-fit indices (CFI = 0.933, TLI = 0.924, RMSEA = 0.075, SRMR = 0.081). Internal consistency was satisfactory across domains, with Cronbach's alpha ranging from 0.70 to 0.89 and McDonald's omega from 0.75 to 0.93. Test-retest reliability demonstrated good temporal stability. Patients with HypoPT reported significantly higher symptom burden compared with both hypothyroid patients and healthy controls across several domains.</p><p><strong>Conclusions: </strong>The Italian version of the HPQ-28 demonstrates good psychometric properties and represents a reliable disease-specific instrument for assessing symptom burden in patients with hypoparathyroidism in both clinical practice and research settings.</p>","PeriodicalId":48802,"journal":{"name":"Journal of Endocrinological Investigation","volume":" ","pages":"2803-2811"},"PeriodicalIF":3.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148259922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Portrait of Lili Elbe born Einer Wegener.","authors":"F Trimarchi, E Martino, L Bartalena","doi":"10.1007/s40618-026-02934-z","DOIUrl":"10.1007/s40618-026-02934-z","url":null,"abstract":"","PeriodicalId":48802,"journal":{"name":"Journal of Endocrinological Investigation","volume":" ","pages":"3105-3107"},"PeriodicalIF":3.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148139442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of TGF-β1/Smad signaling reverses the dedifferentiated phenotype of thyroid cancer cells in three-dimensional culture.","authors":"Li Zhang, Wenjing Gao, Shichen Xu, Hongxun Wu, Yun Zhu, Botao Huang, Xian Cheng, Jing Wu, Huixin Yu, Jiandong Bao, Zichao Zhang","doi":"10.1007/s40618-026-02963-8","DOIUrl":"10.1007/s40618-026-02963-8","url":null,"abstract":"<p><strong>Purpose: </strong>Thyroid cancer is the most common malignancy of the endocrine system, with a rising global incidence. Radioactive iodine (RAI) therapy with ¹³¹I is used post-surgery to ablate residual thyroid tissue and cancer cells in differentiated thyroid cancer. However, in radioiodine-refractory cases, tumor cells often undergo dedifferentiation and develop RAI resistance, severely limiting therapeutic efficacy. Therefore, elucidating the mechanisms underlying dedifferentiation and developing strategies to restore differentiation have become a hot topic in thyroid cancer research. In this study, a three-dimensional (3D) culture model of TPC-1 thyroid cancer cells was developed using hanging drop and low-adhesion methods to mimic the dedifferentiation process in vitro. Cells cultured under 3D conditions exhibited typical dedifferentiated features, including upregulation of cancer stem cell markers, downregulation of thyroid functional proteins, and impaired radioiodine uptake. Through integrated bioinformatic analysis and immunohistochemical staining of in-house papillary thyroid carcinoma (PTC) samples, we identified transforming growth factor beta 1 (TGF-β1) as a potent inducer of thyroid cancer dedifferentiation. The TGF-β1/Smad signaling pathway was activated in PTC tissues, where it played a critical role in regulating tumor stemness and the expression of iodine-metabolizing proteins. Galunisertib, a TGF-β type I receptor kinase inhibitor, effectively blocked TGF-β1 signaling in spheroids, suppressed cancer stem cell marker expression, and enhanced radioiodine uptake through upregulation of thyroid functional proteins, establishing TGF-β1 as a therapeutic target in thyroid cancer. Collectively, the established 3D culture model serves as a robust platform for investigating dedifferentiation in thyroid cancer and provides a basis for developing novel therapies against radioiodine resistance.Plain Language.</p>","PeriodicalId":48802,"journal":{"name":"Journal of Endocrinological Investigation","volume":" ","pages":"2693-2707"},"PeriodicalIF":3.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148392318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Early in, early out: reproductive lifespan timing and cardiometabolic risk in women.","authors":"Valeria Calcaterra, Rossella E Nappi, Laura Cucinella, Ilaria Anna Maria Scavone, Giorgia E Parrotta, Gianvincenzo Zuccotti","doi":"10.1007/s40618-026-02958-5","DOIUrl":"10.1007/s40618-026-02958-5","url":null,"abstract":"","PeriodicalId":48802,"journal":{"name":"Journal of Endocrinological Investigation","volume":" ","pages":"2671"},"PeriodicalIF":3.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148377669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low work ability and high disability burden in Cushing's syndrome: a multicenter cohort study.","authors":"Annika Steinkogler, Stephanie Zopp, Kathrin Moser, Júnia R O L Schweizer, Isabel Stüfchen, Friederike Völter, Katrin Ritzel, German Rubinstein, Leah T Braun, Marily Theodoropoulou, Birgit Linkohr, Rolf Holle, Tina Kienitz, Marcus Quinkler, Martin Reincke, Elisabeth Nowak","doi":"10.1007/s40618-026-02966-5","DOIUrl":"10.1007/s40618-026-02966-5","url":null,"abstract":"<p><strong>Context: </strong>The socio-occupational burden of Cushing's syndrome (CS) remains underrecognised. In clinical practice, surgically treated patients are often considered recovered, potentially overlooking persistent impairment.</p><p><strong>Purpose: </strong>To evaluate work ability, social and employment status in newly diagnosed and remitted CS.</p><p><strong>Methods: </strong>National observational study with two arms: a monocentric prospective study of patients evaluated for suspected endogenous glucocorticoid excess (cohort 1), and a multicenter cross-sectional study of patients in remission from CS, comparing those with recovered versus persistent adrenal insufficiency (cohort 2). All participants underwent standardised assessments and completed validated questionnaires on socioeconomic status, work ability, and fatigue.</p><p><strong>Results: </strong>In cohort 1, individuals with active CS (n = 28) and excluded CS (n = 56) had comparable comorbidities, education, and employment. However, work ability scores were lower in active CS (median 22.5 vs. 28.5, p = 0.008) and correlated inversely with biochemical cortisol excess. In multivariable analyses, active CS and depression were independently associated with lower work ability, whereas older age and depression were independently associated with fatigue severity. In cohort 2 (n = 89, 39 with recovered, 50 with persistent adrenal insufficiency), overall employment was 69%. Poor work ability was common (42% with recovered vs. 58% with persistent adrenal insufficiency) and weekly working hours were lower in those with persistent insufficiency (33 h vs. 39 h, p = 0.051). Overall, illness-related absences occurred in 76% during the preceding year, disability was recognised in 47%, and 15% received reduced earning capacity pensions. Fatigue correlated negatively with work ability (r = - 0.73, p < 0.0001).</p><p><strong>Conclusion: </strong>There is an unmet need for structured rehabilitation and reintegration in CS.</p>","PeriodicalId":48802,"journal":{"name":"Journal of Endocrinological Investigation","volume":" ","pages":"2721-2734"},"PeriodicalIF":3.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13627271/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148406449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiomics profiling of bone in the Dpp3-deficient mice unveils altered protein and lipid composition.","authors":"Emilia Bevacqua, Federica Violi, Valentina Granata, Fabio Bedin, Mariarosaria Santillo, Ciro Menale, Gherardo Mazziotti, Cristina Sobacchi","doi":"10.1007/s40618-026-02949-6","DOIUrl":"10.1007/s40618-026-02949-6","url":null,"abstract":"<p><strong>Purpose: </strong>Bone is a unique specialized connective tissue comprising inorganic and organic components which continuously undergoes remodeling through the activity of anabolic and catabolic pathways. Peptidases are enzymes cleaving peptide bonds in a broad range of substrates and hence involved in many pathophysiological mechanisms. We previously reported that lack of Dpp3 in the mouse model results in bone loss and here we aimed to establish whether it also affected bone matrix composition.</p><p><strong>Methods: </strong>We performed proteomic and lipidomics analysis of the flushed bone of 6-month-old wild type (WT) and Dpp3 knock-out (ko) male mice (4 mice/genotype); Western blot analysis of selected upregulated proteins and gene expression analysis of genes potentially involved in the identified pathways.</p><p><strong>Results: </strong>We found that Dpp3 deficiency was associated with a proteomic signature in the bone matrix consistent with sustained oxidative stress and altered matrix turnover and pointing to a metabolic adaptation within the skeletal tissue. Accordingly, lack of Dpp3 resulted in a shift in lipid composition in the bone matrix, with enrichment of specific structural lipids and lack of others for energy production.</p><p><strong>Conclusion: </strong>Our work confirms the importance of DPP3 in the context of bone homeostasis and sheds some light on the matrix composition of DPP3-depleted bone. Owing to the foreseen translational implications of this evidence, further investigation is deserved to complete a comprehensive characterization.</p>","PeriodicalId":48802,"journal":{"name":"Journal of Endocrinological Investigation","volume":" ","pages":"2897-2912"},"PeriodicalIF":3.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13627175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148664699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of metreleptin treatment in congenital generalized lipodystrophy: a retrospective analysis from the MENA region.","authors":"Majid Alfadhel, Afaf Alsagheir, Azza Al Shidhani, Ahmed Ali Nahari, Yasser Binafif, Najya Attia, Nasser Aljuhani, Khulood Najdeyah, Haya Alkhayyat, Jamal Al Jubeh, Imad Brema, Najah Douba, Elham Alamiri, Mouza Al Yahyaei, Saleha Babli, Mohammed Alqahtani, Amal Al-Qahtani, Ibrahim Al Alwan, Nadia Hergli, Saif Al Yaarubi, Rebecca J Brown","doi":"10.1007/s40618-026-02977-2","DOIUrl":"10.1007/s40618-026-02977-2","url":null,"abstract":"<p><strong>Purpose: </strong>Congenital generalized lipodystrophy (CGL) is characterized by near-total loss of body fat, leptin deficiency, and severe metabolic complications. Clinical data show that metreleptin improves metabolic control in CGL; however, data from the Middle East and North Africa (MENA) is limited. We assessed the real-world effectiveness and safety of metreleptin in patients with CGL from this region.</p><p><strong>Methods: </strong>We conducted a multicenter, retrospective chart review of patients with CGL. Baseline, 6 ± 2months (short-term), 2 ± 1years (long-term), and >3 years follow-up data were analyzed. Median changes from baseline were calculated for short- and long-term assessments; >3 years data were reviewed individually. Safety was evaluated up to 90 days after last dose.</p><p><strong>Results: </strong>Thirty-eight patients were included (82% female; median age at baseline, 6.3 years). Median treatment duration with metreleptin was 25 months (max dose, 10 mg/day). Significant short-term median reductions from baseline were observed for HbA1c (- 1.4%; n = 26), fasting plasma glucose (- 0.5 mmol/L; n = 21); fasting triglycerides (TG; -1.5 mmol/L; n = 26), alanine aminotransferase (- 18 IU/L, n = 27) and aspartate aminotransferase (- 7 IU/L, n = 27) (all p ≤ 0.02). These reductions were significant at long-term follow-up (p < 0.01) except for aspartate aminotransferase. At short-term follow-up, 50.0% of patients achieved  ≥1%  reduction in HbA1c and 65.4% had a  ≥30% reduction in TG; corresponding long-term patient proportions were 46.7% and 61.5%. Most patients with >3 years follow-up showed improvement/maintenance of metabolic parameters. Overall, metreleptin was well tolerated with no new safety signals detected.</p><p><strong>Conclusions: </strong>Our findings support early intervention with metreleptin for sustained diabetes and hypertriglyceridemia control in CGL.</p>","PeriodicalId":48802,"journal":{"name":"Journal of Endocrinological Investigation","volume":" ","pages":"2951-2962"},"PeriodicalIF":3.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13627170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148594325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of estroprogestin therapies on bone health from adolescence to postmenopause.","authors":"Guabello G, Federici S, Carrara S, Ruotolo E, Rossi A, Bertini J, Bonomi M, Grandi G, Corbetta S","doi":"10.1007/s40618-025-02802-2","DOIUrl":"10.1007/s40618-025-02802-2","url":null,"abstract":"<p><strong>Background: </strong>Estrogens are fundamental to bone health, exerting life-long effects onbone metabolism. They regulate skeletal growth and maturation during adolescence andmaintain bone remodeling in adulthood. The decline in estrogen levels during perimenopauseand postmenopause leads to bone mass loss. Emerging evidence also supports a role forprogestins in bone metabolism. Several estrogen-progestins formulations are available andwidely used for contraception in fertile women and as hormone replacement therapy (HRT) incases of primary or secondary ovarian insufficiency as well as in physiologic menopause.Advances in both synthetic and natural preparations allowed for more personalized treatmentapproaches. When selecting estrogen-progestin therapies, it is essential to consider their impacton bone health and remodelling.</p><p><strong>Objective: </strong>This narrative review examines the effects of variousestrogen-progestin regimens on bone metabolism across the female lifespan, focusing on mechanisms of action, safety profiles, and clinical applications. Here we show that combined oralcontraceptives (COCs) are generally safe for bone mineral density (BMD) in adult women;however, caution is advised in adolescence, especially with very low-dose estrogen formulations.In hypogonadal women, postmenopausal hormone replacement therapy (HRT) is key forosteoporosis prevention. Physiological regimens, preferably transdermal estrogen at doseshigher than those used in typical postmenopausal therapy, may offer better bone protection.Additionally, oral gonadotropin-releasing hormone receptor (GnRH-R) antagonists combinedwith add-back therapy represent a novel long-term option for managing uterine fibroids andendometriosis without compromising BMD. In postmenopausal women, both HRT and selectiveestrogen receptor modulators (SERMs) effectively reduce fracture risk and support bone health.</p><p><strong>Main results & implications: </strong>Optimizing therapeutic strategies to balance efficacy and safety, iscritical to ensuring personalized care that preserves bone health and enhances quality of lifeacross a woman's lifespan.</p>","PeriodicalId":48802,"journal":{"name":"Journal of Endocrinological Investigation","volume":" ","pages":"2611-2626"},"PeriodicalIF":3.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13627173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146221756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Body mass index outperforms the Rotterdam criteria in defining phenotypic heterogeneity in polycystic ovary syndrome: a multicenter study from the Italian PCOS registry (PCOSOUTCOME.net).","authors":"Alessandra Gambineri, Silvia Federici, Elisa Maseroli, Laura Guccione, Marco Bonomi, Anna Maria Fulghesu, Roberta Giordano, Roberto Mioni, Rosario Pivonello, Laura Rotolo, Chiara Sabbadin, Carla Scaroni, Massimo Tonacchera, Herbert Valensise, Nunzia Verde, Linda Vignozzi, Paolo Moghetti, Costanzo Moretti","doi":"10.1007/s40618-026-02946-9","DOIUrl":"10.1007/s40618-026-02946-9","url":null,"abstract":"<p><strong>Purpose: </strong>Polycystic ovary syndrome (PCOS) is a common and highly heterogeneous endocrine-metabolic disorder. The Rotterdam criteria identify four diagnostic phenotypes; however, it remains unclear whether these phenotypes or body mass index (BMI) better predict metabolic risk. The PCOSOUTCOME.net registry collects data from multiple Italian centers and provides an opportunity to compare the effectiveness of Rotterdam phenotypes versus BMI in characterizing the clinical, metabolic, and psychological heterogeneity of women with PCOS.</p><p><strong>Methods: </strong>We included 1,314 Caucasian women of reproductive age with PCOS. Participants were stratified according to Rotterdam phenotypes and BMI categories (normal weight, overweight, and obesity; and BMI < 27 kg/m² vs. ≥ 27 kg/m²). Clinical, hormonal, metabolic, gynecological, and psychological parameters were assessed and compared across subgroups.</p><p><strong>Results: </strong>No significant differences in BMI or in the prevalence of metabolic complications (dyslipidemia, glucose intolerance, hypertension, and metabolic syndrome) were observed among the four Rotterdam phenotypes, although anxiety scores were highest in phenotype A. In contrast, BMI-based stratification identified clear differences in metabolic markers: women with obesity or a BMI ≥ 27 kg/m² showed a higher prevalence of all metabolic complications, as well as higher free androgen index (FAI) and hirsutism scores.</p><p><strong>Conclusions: </strong>In this multicenter cohort, Rotterdam phenotypes failed to discriminate metabolic risk, whereas BMI-based stratification proved more informative in identifying cardiometabolic complications. Moreover, obesity in PCOS identifies a distinct hyperandrogenic phenotype. These findings underscore the need to integrate BMI into the classification of PCOS to better capture patient heterogeneity, with potential implications for metabolic assessment and risk stratification.</p>","PeriodicalId":48802,"journal":{"name":"Journal of Endocrinological Investigation","volume":" ","pages":"2813-2823"},"PeriodicalIF":3.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13627167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148851796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early in, early out: reproductive lifespan timing and cardiometabolic risk in women.","authors":"Valeria Calcaterra, Rossella E Nappi, Laura Cucinella, Ilaria Anna Maria Scavone, Giorgia E Parrotta, Gianvincenzo Zuccotti","doi":"10.1007/s40618-026-02890-8","DOIUrl":"10.1007/s40618-026-02890-8","url":null,"abstract":"<p><strong>Purpose: </strong>The timing of the biological reproductive span, defined by age at menarche and age at menopause which mark overall reproductive lifespan, has emerged as a clinically relevant red flag of cardio-metabolic vulnerability in women. Beyond reproductive function, these milestones reflect interconnected trajectories of ovarian, metabolic, and vascular ageing, offering a life-course framework for cardiovascular risk identification.</p><p><strong>Methods: </strong>The present narrative review synthesized evidence from PubMed, Scopus, and Web of Science through December 2025 using terms related to reproductive timing, ovarian aging, cardiovascular disease, and metabolic risk. Observational studies, meta-analyses, mechanistic investigations, and clinical guidelines were included. Evidence was critically appraised to integrate epidemiological associations with biological mechanisms and clinical implications.</p><p><strong>Results: </strong>Early menarche is consistently associated with insulin resistance, dyslipidemia, hypertension, type 2 diabetes, coronary heart disease, stroke, and increased mortality. A U-shaped relationship has also been reported, with very late menarche conferring excess risk. Early menopause and primary ovarian insufficiency (POI) increase cardiovascular risk through early estrogen deprivation, endothelial dysfunction, inflammation, and accelerated vascular aging. A shortened reproductive lifespan independently predicts higher cardiovascular events and mortality. These associations reflect not only cumulative estrogen exposure but also shared genetic susceptibility, adiposity-related pathways, early-life programming, and chronic metabolic stress.</p><p><strong>Conclusion: </strong>Reproductive timing represents a key sex-specific dimension of cardiovascular risk. Although POI is recognized in guidelines, systematic consideration of age at menarche and reproductive lifespan may improve early detection, risk stratification, and personalized prevention across the female life course. Recognizing reproductive history as a determinant of cardiovascular ageing is essential to advancing truly sex-specific prevention.</p>","PeriodicalId":48802,"journal":{"name":"Journal of Endocrinological Investigation","volume":" ","pages":"2657-2670"},"PeriodicalIF":3.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147647178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}