{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T14:19:27Z","timestamp":1764166767752,"version":"3.46.0"},"reference-count":59,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T00:00:00Z","timestamp":1764115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Tixupharma srl using private internal funds"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: Genitourinary syndrome of menopause (GSM), previously termed vulvovaginal atrophy (VVA), is a prevalent hypoestrogenic condition characterized by genital, sexual, and urinary symptoms. Although hormonal therapies are effective, many women are unwilling or unsuitable to use them. Spermidine hyaluronate (Spd-HA) has been reported to be effective in the treatment of vulvodynia and is currently under investigation for stress urinary incontinence. The aim of this study was to evaluate the efficacy of Spd-HA gel on the signs and symptoms of GSM. Materials and Methods: Five postmenopausal women with GSM presenting with vulvovaginal atrophy were enrolled in this prospective, single-arm, pilot study. They applied Spd-HA gel locally for eight weeks (three times\/week for the first 4 weeks, followed by two times\/week for the next 4 weeks). Vulvovaginal signs and symptoms were assessed at baseline (V1), 4 weeks (V2), and 8 weeks (V3) using the most bothersome symptoms (MBS), vaginal health index (VHI), and maturation index (MI) and value (MV). Results: Spd-HA gel was associated with MBS score improvement from baseline to week 8 [from (5.00 \u00b1 2.00) to (1.60 \u00b1 1.52)]. VHI score and MI improved from baseline to week 8. Compared to literature data, improvement in MVs obtained in women who received Spd-HA was greater than those obtained by hydrating products, but lower than those observed in women with estrogen or prasterone therapy. Conclusions: This preliminary experience suggests that Spd-HA gel ameliorates the vulvovaginal component of GSM. It may represent a promising non-hormonal option for women with GSM who are unwilling or unsuitable to receive hormonal therapy, warranting confirmation in larger controlled trials.<\/jats:p>","DOI":"10.3390\/medicina61122104","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T13:56:34Z","timestamp":1764165394000},"page":"2104","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Topical Spermidine Hyaluronate (Spd-HA) in Vulvovaginal Atrophy: A Preliminary Study"],"prefix":"10.3390","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0304-4274","authenticated-orcid":false,"given":"Irene","family":"Porcari","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, AOUI Verona, University of Verona, 37126 Verona, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michela","family":"Carena Maini","sequence":"additional","affiliation":[{"name":"Private Medical Practice, 20159 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlo Angelo","family":"Ghisalberti","sequence":"additional","affiliation":[{"name":"Research Department, Tixupharma Srl, 20134 Milan, Italy"},{"name":"Department of Biomedical Sciences for Health, University of Milan, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0531-3906","authenticated-orcid":false,"given":"Caterina","family":"Tezze","sequence":"additional","affiliation":[{"name":"Research Department, Tixupharma Srl, 20134 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5885-0436","authenticated-orcid":false,"given":"Erica","family":"Trimarchi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, AOUI Verona, University of Verona, 37126 Verona, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandra","family":"Graziottin","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, AOUI Verona, University of Verona, 37126 Verona, Italy"},{"name":"Centre of Gynaecology and Medical Sexology, Department of Obstetrics and Gynaecology, San Raffaele Resnati Hospital, 20122 Milan, Italy"},{"name":"Alessandra Graziottin Foundation for the Cure and Care of Pain in Women, NPO, 20122 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2109-6182","authenticated-orcid":false,"given":"Mariachiara","family":"Bosco","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, AOUI Verona, University of Verona, 37126 Verona, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8434-1587","authenticated-orcid":false,"given":"Chiara","family":"Casprini","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, AOUI Verona, University of Verona, 37126 Verona, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5840-699X","authenticated-orcid":false,"given":"Simone","family":"Garzon","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, AOUI Verona, University of Verona, 37126 Verona, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4456-0822","authenticated-orcid":false,"given":"Stefano","family":"Uccella","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, AOUI Verona, University of Verona, 37126 Verona, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"qeaf055","DOI":"10.1093\/sxmrev\/qeaf055","article-title":"Genitourinary Syndrome of Menopause (GSM): Recommendations from the Fifth International Consultation on Sexual Medicine (ICSM 2024)","volume":"13","author":"Simon","year":"2025","journal-title":"Sex. Med. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1080\/13697137.2023.2171287","article-title":"Validation of a Clinical Tool for Vestibular Trophism in Postmenopausal Women","volume":"26","author":"Murina","year":"2023","journal-title":"Climacteric"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Nappi, R.E., Martini, E., Cucinella, L., Martella, S., Tiranini, L., Inzoli, A., Brambilla, E., Bosoni, D., Cassani, C., and Gardella, B. (2019). Addressing Vulvovaginal Atrophy (VVA)\/Genitourinary Syndrome of Menopause (GSM) for Healthy Aging in Women. Front. Endocrinol., 10.","DOI":"10.3389\/fendo.2019.00561"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1097\/GME.0000000000000329","article-title":"Vulvovaginal Atrophy Terminology Consensus Conference Panel Genitourinary Syndrome of Menopause: New Terminology for Vulvovaginal Atrophy from the International Society for the Study of Women\u2019s Sexual Health and the North American Menopause Society","volume":"21","author":"Portman","year":"2014","journal-title":"Menopause"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"The NAMS 2020 GSM Position Statement Editorial Panel (2020). The 2020 Genitourinary Syndrome of Menopause Position Statement of The North American Menopause Society. Menopause, 27, 976\u2013992.","DOI":"10.1097\/GME.0000000000001609"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1097\/GME.0000000000002028","article-title":"The 2022 Hormone Therapy Position Statement of The North American Menopause Society","volume":"29","author":"Faubion","year":"2022","journal-title":"Menopause"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.jsxm.2021.12.010","article-title":"CO2-Laser Therapy and Genitourinary Syndrome of Menopause: A Systematic Review and Meta-Analysis","volume":"19","author":"Filippini","year":"2022","journal-title":"J. Sex. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.21037\/apm-24-77","article-title":"Sexual Health after Breast Cancer: A Clinical Practice Review","volume":"13","author":"Kennedy","year":"2024","journal-title":"Ann. Palliat. Med."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"(2024). New Drug: Prasterone for Vulvar and Vaginal Atrophy in Postmenopausal Women. Aust. Prescr., 47, 164.","DOI":"10.18773\/austprescr.2024.041"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1515\/hmbci-2015-0044","article-title":"Effect of Intravaginal Dehydroepiandrosterone (DHEA) on the Female Sexual Function in Postmenopausal Women: ERC-230 Open-Label Study","volume":"25","author":"Bouchard","year":"2016","journal-title":"Horm. Mol. Biol. Clin. Investig."},{"key":"ref_11","first-page":"643","article-title":"Evaluating the Efficacy of Vaginal Dehydroepiandosterone for Vaginal Symptoms in Postmenopausal Cancer Survivors: NCCTG N10C1 (Alliance)","volume":"26","author":"Barton","year":"2018","journal-title":"Support. Care Cancer"},{"key":"ref_12","first-page":"193","article-title":"Treating and Managing Urinary Incontinence: Evolving and Potential Multicomponent Medical and Lifestyle Interventions","volume":"15","author":"Taithongchai","year":"2023","journal-title":"Res. Rep. Urol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"480","DOI":"10.23736\/S2724-606X.21.04841-7","article-title":"Treatment of Vulvo-Vaginal Atrophy with Hyaluronate-Based Gel: A Randomized Controlled Study","volume":"74","author":"Nappi","year":"2022","journal-title":"Minerva Obstet. Gynecol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.maturitas.2021.03.002","article-title":"Efficacy and Safety of a New Vaginal Gel for the Treatment of Symptoms Associated with Vulvovaginal Atrophy in Postmenopausal Women: A Double-Blind Randomized Placebo-Controlled Study","volume":"147","author":"Caruso","year":"2021","journal-title":"Maturitas"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1080\/07853890.2021.1974083","article-title":"Efficacy and Safety of Prolonged-Release Hyaluronic Acid Derivative Vaginal Application in the Postpartum Period: A Prospective Randomised Clinical Trial","volume":"53","author":"Gustavino","year":"2021","journal-title":"Ann. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"108232","DOI":"10.1016\/j.maturitas.2025.108232","article-title":"Effects of Vaginal DHEA on Stress Urinary Incontinence in Postmenopausal Women with Vulvovaginal Atrophy","volume":"196","author":"Misasi","year":"2025","journal-title":"Maturitas"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1080\/13697137.2021.1898580","article-title":"Hyaluronic Acid in Vulvar and Vaginal Administration: Evidence from a Literature Systematic Review","volume":"24","author":"Buzzaccarini","year":"2021","journal-title":"Climacteric"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1055\/s-0031-1296715","article-title":"Open, Non-Controlled Clinical Studies to Assess the Efficacy and Safety of a Medical Device in Form of Gel Topically and Intravaginally Used in Postmenopausal Women with Genital Atrophy","volume":"56","author":"Morali","year":"2011","journal-title":"Arzneimittelforschung"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"835","DOI":"10.3109\/01443615.2015.1014326","article-title":"Non-Hormonal Treatment of Vulvo-Vaginal Atrophy-Related Symptoms in Post-Menopausal Women","volume":"35","author":"Tersigni","year":"2015","journal-title":"J. Obstet. Gynaecol."},{"key":"ref_20","first-page":"e44191","article-title":"Comparison of the Efficacy of Vaginal Hyaluronic Acid to Estrogen for the Treatment of Vaginal Atrophy in Postmenopausal Women: A Systematic Review","volume":"15","author":"Albalawi","year":"2023","journal-title":"Cureus"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2317268","DOI":"10.1080\/09513590.2024.2317268","article-title":"Prospective, Multicenter, Uncontrolled Study on the Effectiveness and Safety of a Hyaluronic Acid Water-Based Vaginal Lubricant in Alleviating Vaginal Dryness and Dyspareunia","volume":"40","author":"Bergamaschi","year":"2024","journal-title":"Gynecol. Endocrinol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"363","DOI":"10.3109\/13697137.2014.899347","article-title":"A 12-Week Treatment with Fractional CO2 Laser for Vulvovaginal Atrophy: A Pilot Study","volume":"17","author":"Salvatore","year":"2014","journal-title":"Climacteric"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.ejogrb.2022.01.021","article-title":"Polycarbophil Vaginal Moisturizing Gel versus Hyaluronic Acid Gel in Women Affected by Vaginal Dryness in Late Menopausal Transition: A Prospective Randomized Trial","volume":"270","author":"Cagnacci","year":"2022","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1974","DOI":"10.4236\/ojog.2023.1312167","article-title":"Clinical Significance of Topical Spermidine Hyaluronate in Vestibulodynia: An Early Appraisal","volume":"13","author":"Murina","year":"2023","journal-title":"Open J. Obstet. Gynecol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.biocel.2009.07.009","article-title":"Modulation of Cellular Function by Polyamines","volume":"42","author":"Igarashi","year":"2010","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1159\/000356748","article-title":"Molecular Basis of the \u201canti-Aging\u201d Effect of Spermidine and Other Natural Polyamines\u2014A Mini-Review","volume":"60","author":"Minois","year":"2014","journal-title":"Gerontology"},{"key":"ref_27","first-page":"469","article-title":"Classic Pages in Obstetrics and Gynecology. Observationes\u2026de Natis \u00e8 Semine Genitali Animalculis. Antoni Van Leeuwenhoek. Philosophical Transactions of the Royal Society (London), Vol. 12, pp. 1040\u20131043, 1678\u20131679","volume":"131","author":"Leeuwenhoek","year":"1978","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1210\/er.2011-0012","article-title":"Polyamines on the Reproductive Landscape","volume":"32","author":"Palin","year":"2011","journal-title":"Endocr. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"20803","DOI":"10.1016\/S0021-9258(18)54780-3","article-title":"Estimation of Polyamine Binding to Macromolecules and ATP in Bovine Lymphocytes and Rat Liver","volume":"266","author":"Watanabe","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"eaan2788","DOI":"10.1126\/science.aan2788","article-title":"Spermidine in Health and Disease","volume":"359","author":"Madeo","year":"2018","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1093\/ecco-jcc\/jjad058","article-title":"Spermidine Ameliorates Colitis via Induction of Anti-Inflammatory Macrophages and Prevention of Intestinal Dysbiosis","volume":"17","author":"Niechcial","year":"2023","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.freeradbiomed.2020.03.029","article-title":"Spermidine Rescues the Deregulated Autophagic Response to Oxidative Stress of Osteoarthritic Chondrocytes","volume":"153","author":"Cetrullo","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"71","DOI":"10.4331\/wjbc.v4.i3.71","article-title":"Potent Trophic Activity of Spermidine Supramolecular Complexes in In Vitro Models","volume":"4","author":"Ghisalberti","year":"2013","journal-title":"World J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Murina, F., Graziottin, A., Toni, N., Schettino, M.T., Bello, L., Marchi, A., Del Bravo, B., Gambini, D., Tiranini, L., and Nappi, R.E. (2024). Clinical Evidence Regarding Spermidine\u2013Hyaluronate Gel as a Novel Therapeutic Strategy in Vestibulodynia Management. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16111448"},{"key":"ref_35","unstructured":"Ziegler, W.J., and Perren, S.M. (1995). Standards, guidelines and principles for clinical trials: Medical products. Swiss Surg., 81\u201383. Available online: https:\/\/pubmed.ncbi.nlm.nih.gov\/8581810\/."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1097\/gme.0b013e318182f84b","article-title":"Measuring Symptom Relief in Studies of Vaginal and Vulvar Atrophy: The Most Bothersome Symptom Approach","volume":"15","author":"Ettinger","year":"2008","journal-title":"Menopause"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1016\/0378-5122(95)00956-6","article-title":"Urogenital Ageing: An Old Problem Newly Recognized","volume":"22","author":"Bachmann","year":"1995","journal-title":"Maturitas"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1080\/13697137.2018.1446930","article-title":"The European Vulvovaginal Epidemiological Survey (EVES): Prevalence, Symptoms and Impact of Vulvovaginal Atrophy of Menopause","volume":"21","author":"Palacios","year":"2018","journal-title":"Climacteric"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1097\/gme.0b013e31816c5541","article-title":"Vaginal Maturation Index Self-Sample Collection in Mid-Life Women: Acceptability and Correlation with Physician-Collected Samples","volume":"15","author":"Hess","year":"2008","journal-title":"Menopause"},{"key":"ref_40","first-page":"249","article-title":"The Maturation Value","volume":"11","author":"Meisels","year":"1967","journal-title":"Acta Cytol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/s00404-010-1382-8","article-title":"The Comparison of Hyaluronic Acid Vaginal Tablets with Estradiol Vaginal Tablets in the Treatment of Atrophic Vaginitis: A Randomized Controlled Trial","volume":"283","author":"Ekin","year":"2011","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1097\/gme.0b013e31819e8e2d","article-title":"Intravaginal Dehydroepiandrosterone (Prasterone), a Physiological and Highly Efficient Treatment of Vaginal Atrophy","volume":"16","author":"Labrie","year":"2009","journal-title":"Menopause"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1097\/GME.0000000000000590","article-title":"Venous Thromboembolism and Cardiovascular Disease Complications in Menopausal Women Using Transdermal versus Oral Estrogen Therapy","volume":"23","author":"Simon","year":"2016","journal-title":"Menopause"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1136\/jcp.55.6.446","article-title":"The Effect of Replens(R) on Vaginal Cytology in the Treatment of Postmenopausal Atrophy: Cytomorphology versus Computerised Cytometry","volume":"55","author":"Hanselaar","year":"2002","journal-title":"J. Clin. Pathol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Alvisi, S., Gava, G., Orsili, I., Giacomelli, G., Baldassarre, M., Seracchioli, R., and Meriggiola, M.C. (2019). Vaginal Health in Menopausal Women. Medicina, 55.","DOI":"10.3390\/medicina55100615"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"107950","DOI":"10.1016\/j.maturitas.2024.107950","article-title":"Vulvovaginal Atrophy in Women with and without a History of Breast Cancer: Baseline Data from the Patient Satisfaction Study (PEONY) in Italy","volume":"183","author":"Meriggiola","year":"2024","journal-title":"Maturitas"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"18","DOI":"10.3109\/13697137.2013.801736","article-title":"Androgen Therapy in Women, beyond Libido","volume":"16","author":"Davis","year":"2013","journal-title":"Climacteric"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1016\/j.jsxm.2019.07.012","article-title":"Global Consensus Position Statement on the Use of Testosterone Therapy for Women","volume":"16","author":"Davis","year":"2019","journal-title":"J. Sex. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1042\/bst0320416","article-title":"Hierarchical Assembly of Cell\u2013Matrix Adhesion Complexes","volume":"32","author":"Cohen","year":"2004","journal-title":"Biochem. Soc. Trans."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Jiang, D., Guo, Y., Niu, C., Long, S., Jiang, Y., Wang, Z., Wang, X., Sun, Q., Ling, W., and An, X. (2023). Exploration of the Antioxidant Effect of Spermidine on the Ovary and Screening and Identification of Differentially Expressed Proteins. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24065793"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4329","DOI":"10.1091\/mbc.e05-02-0170","article-title":"Cell Adhesion Strengthening: Contributions of Adhesive Area, Integrin Binding, and Focal Adhesion Assembly","volume":"16","author":"Gallant","year":"2005","journal-title":"Mol. Biol. Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"C801","DOI":"10.1152\/ajpcell.00620.2008","article-title":"Polyamines Regulate E-Cadherin Transcription through c-Myc Modulating Intestinal Epithelial Barrier Function","volume":"296","author":"Liu","year":"2009","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/S0006-3495(00)76279-5","article-title":"Cell Movement Is Guided by the Rigidity of the Substrate","volume":"79","author":"Lo","year":"2000","journal-title":"Biophys. J."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Mechulam, A., Chernov, K.G., Mucher, E., Hamon, L., Curmi, P.A., and Pastr\u00e9, D. (2009). Polyamine Sharing between Tubulin Dimers Favours Microtubule Nucleation and Elongation via Facilitated Diffusion. PLoS Comput. Biol., 5.","DOI":"10.1371\/journal.pcbi.1000255"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1038\/ncb1975","article-title":"Induction of Autophagy by Spermidine Promotes Longevity","volume":"11","author":"Eisenberg","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"35","DOI":"10.6118\/jmm.24022","article-title":"Assessing the Noninferiority of the Spermidine Hyaluronate Complex Relative to 17\u03b2-Estradiol Treatment in the Ovariectomized Murine Model of Vulvovaginal Atrophy","volume":"31","author":"Ghisalberti","year":"2025","journal-title":"J. Menopausal Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1210\/jc.2004-1223","article-title":"Aging and Estrogen Effects on Transcervical-Transvaginal Epithelial Permeability","volume":"90","author":"Gorodeski","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Kang, H.T., Lee, K.B., Kim, S.Y., Choi, H.R., and Park, S.C. (2011). Autophagy Impairment Induces Premature Senescence in Primary Human Fibroblasts. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0023367"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1093\/jb\/mvj003","article-title":"Decrease in Polyamines with Aging and Their Ingestion from Food and Drink","volume":"139","author":"Nishimura","year":"2006","journal-title":"J. Biochem."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/61\/12\/2104\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T14:15:02Z","timestamp":1764166502000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/61\/12\/2104"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,26]]},"references-count":59,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["medicina61122104"],"URL":"https:\/\/doi.org\/10.3390\/medicina61122104","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,26]]}}}