{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T16:04:35Z","timestamp":1773504275795,"version":"3.50.1"},"reference-count":40,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T00:00:00Z","timestamp":1709856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PRIN","award":["#2022JJ3LZY"],"award-info":[{"award-number":["#2022JJ3LZY"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Semaphorin 3A (SEMA3A) plays a crucial role in the development, differentiation, and plasticity of specific types of neurons that secrete Gonadotropin-Releasing Hormone (GnRH) and regulates the acquisition and maintenance of reproductive competence in humans and mice. Its insufficient expression has been linked to reproductive disorders in humans, which are characterized by reduced or failed sexual competence. Various mutations, polymorphisms, and alternatively spliced variants of SEMA3A have been associated with infertility. One of the common causes of infertility in women of reproductive age is diminished ovarian reserve (DOR), characterized by a reduced ovarian follicular pool. Despite its clinical significance, there are no universally accepted diagnostic criteria or therapeutic interventions for DOR. In this study, we analyzed the SEMA3A plasma levels in 77 women and investigated their potential role in influencing fertility in patients with DOR. The results revealed that the SEMA3A levels were significantly higher in patients with DOR than in healthy volunteers. Furthermore, the SEMA3A levels were increased in patients who underwent fertility treatment and had positive Beta-Human Chorionic Gonadotropin (\u03b2HCG) values (\u03b2+) after controlled ovarian stimulation (COS) compared to those who had negative \u03b2HCG values (\u03b2\u2212). These findings may serve as the basis for future investigations into the diagnosis of infertility and emphasize new possibilities for the SEMA3A-related treatment of sexual hormonal dysfunction that leads to infertility.<\/jats:p>","DOI":"10.3390\/life14030358","type":"journal-article","created":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T03:52:11Z","timestamp":1709869931000},"page":"358","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Semaphorin 3A Increases in the Plasma of Women with Diminished Ovarian Reserve Who Respond Better to Controlled Ovarian Stimulation"],"prefix":"10.3390","volume":"14","author":[{"given":"Michela","family":"Palese","sequence":"first","affiliation":[{"name":"Unit of Gynecology, Department of Neuroscience, School of Medicine, University of Naples \u201cFederico II\u201d, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1848-5950","authenticated-orcid":false,"given":"Gabriella","family":"Ferretti","sequence":"additional","affiliation":[{"name":"Unit of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples \u201cFederico II\u201d, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Perruolo","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, University of Naples \u201cFederico II\u201d, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3018-0367","authenticated-orcid":false,"given":"Sara","family":"Serafini","sequence":"additional","affiliation":[{"name":"Unit of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples \u201cFederico II\u201d, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rossana","family":"Sirabella","sequence":"additional","affiliation":[{"name":"Unit of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples \u201cFederico II\u201d, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincenzo","family":"Marrone","sequence":"additional","affiliation":[{"name":"Unit of Gynecology, Department of Neuroscience, School of Medicine, University of Naples \u201cFederico II\u201d, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"De Rosa","sequence":"additional","affiliation":[{"name":"Unit of Gynecology, Department of Neuroscience, School of Medicine, University of Naples \u201cFederico II\u201d, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0454-7946","authenticated-orcid":false,"given":"Laura","family":"Sarno","sequence":"additional","affiliation":[{"name":"Unit of Gynecology, Department of Neuroscience, School of Medicine, University of Naples \u201cFederico II\u201d, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ida","family":"Strina","sequence":"additional","affiliation":[{"name":"Unit of Gynecology, Department of Hygiene and Public Health, School of Medicine, University of Naples \u201cFederico II\u201d, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6719-0107","authenticated-orcid":false,"given":"Carmela","family":"Matrone","sequence":"additional","affiliation":[{"name":"Unit of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples \u201cFederico II\u201d, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maurizio","family":"Guida","sequence":"additional","affiliation":[{"name":"Unit of Gynecology, Department of Neuroscience, School of Medicine, University of Naples \u201cFederico II\u201d, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s10815-017-1058-4","article-title":"Reproductive ovarian testing and the alphabet soup of diagnoses: DOR, POI, POF, POR, and FOR","volume":"35","author":"Pastore","year":"2018","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_2","unstructured":"(2015). Guideline of the European Society of Human Reproduction and Embryology (ESHRE). Management of women with premature ovarian insufficiency."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"672891","DOI":"10.3389\/fnsyn.2021.672891","article-title":"Semaphorins in Adult Nervous System Plasticity and Disease","volume":"13","author":"Carulli","year":"2021","journal-title":"Front. Synaptic Neurosci."},{"key":"ref_4","unstructured":"Matrone, C., and Ferretti, G. (2023). Neuroscience & Biobehavioral Reviews, Elsevier."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1159\/000495916","article-title":"Semaphorin Signaling in GnRH Neurons: From Development to Disease","volume":"109","author":"Oleari","year":"2019","journal-title":"Neuroendocrinology"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Giacobini, P., Parkash, J., Campagne, C., Messina, A., Casoni, F., Vanacker, C., Langlet, F., Hobo, B., Cagnoni, G., and Gallet, S. (2014). Brain endothelial cells control fertility through ovarian-steroid-dependent release of semaphorin 3A. PLoS Biol., 12.","DOI":"10.1371\/journal.pbio.1001808"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"133","DOI":"10.3389\/fendo.2013.00133","article-title":"Semaphorin signaling in the development and function of the gonadotropin hormone-releasing hormone system","volume":"4","author":"Messina","year":"2013","journal-title":"Front. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3292","DOI":"10.1242\/dev.105544","article-title":"Semaphorin signalling during development","volume":"141","author":"Jongbloets","year":"2014","journal-title":"Development"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1093\/hmg\/ddq468","article-title":"Defective gonadotropin-releasing hormone neuron migration in mice lacking SEMA3A signalling through NRP1 and NRP2: Implications for the aetiology of hypogonadotropic hypogonadism","volume":"20","author":"Cariboni","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/B978-0-12-819973-2.00022-8","article-title":"Kallmann syndrome and idiopathic hypogonadotropic hypogonadism: The role of semaphorin signaling on GnRH neurons","volume":"182","author":"Cariboni","year":"2021","journal-title":"Handb. Clin. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1159\/000431021","article-title":"Shaping the Reproductive System: Role of Semaphorins in Gonadotropin-Releasing Hormone Development and Function","volume":"102","author":"Giacobini","year":"2015","journal-title":"Neuroendocrinology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1038\/pr.2014.23","article-title":"Mutation screening of SEMA3A and SEMA7A in patients with congenital hypogonadotropic hypogonadism","volume":"75","author":"Fagerholm","year":"2014","journal-title":"Pediatr. Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Hanchate, N.K., Giacobini, P., Lhuillier, P., Parkash, J., Espy, C., Fouveaut, C., Leroy, C., Baron, S., Campagne, C., and Vanacker, C. (2012). SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome. PLoS Genet., 8.","DOI":"10.1371\/journal.pgen.1002896"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e1816","DOI":"10.1002\/mgg3.1816","article-title":"Analysis of PLXNA1, NRP1, and NRP2 variants in a cohort of patients with isolated hypogonadotropic hypogonadism","volume":"9","author":"Men","year":"2021","journal-title":"Mol. Genet. Genomic. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7752526","DOI":"10.1155\/2021\/7752526","article-title":"Discovery of a Novel Variant of SEMA3A in a Chinese Patient with Isolated Hypogonadotropic Hypogonadism","volume":"2021","author":"Dai","year":"2021","journal-title":"Int. J. Endocrinol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2504660","DOI":"10.1155\/2022\/2504660","article-title":"Identification and Functional Characterization of a Novel Variant in the","volume":"2022","author":"Shu","year":"2022","journal-title":"Int. J. Endocrinol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1093\/humrep\/des022","article-title":"SEMA3A deletion in a family with Kallmann syndrome validates the role of semaphorin 3A in human puberty and olfactory system development","volume":"27","author":"Young","year":"2012","journal-title":"Hum. Reprod."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1530\/REP-21-0486","article-title":"A systematic review and standardized clinical validity assessment of genes involved in female reproductive failure","volume":"163","author":"Volozonoka","year":"2022","journal-title":"Reproduction"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1093\/hmg\/ddy045","article-title":"Sema3a plays a role in the pathogenesis of CHARGE syndrome","volume":"27","author":"Ufartes","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Regev, A., Goldman, S., and Shalev, E. (2007). Semaphorin-4D (Sema-4D), the Plexin-B1 ligand, is involved in mouse ovary follicular development. Reprod. Biol. Endocrinol., 5.","DOI":"10.1186\/1477-7827-5-12"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4934","DOI":"10.1002\/jcp.27294","article-title":"Suppression of SEMA6C promotes preantral follicles atresia with decreased cell junctions in mice ovaries","volume":"234","author":"Yan","year":"2019","journal-title":"J. Cell Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1158\/1535-7163.MCT-09-0664","article-title":"Hormonal regulation and distinct functions of semaphorin-3B and semaphorin-3F in ovarian cancer","volume":"9","author":"Joseph","year":"2010","journal-title":"Mol. Cancer Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"gaad010","DOI":"10.1093\/molehr\/gaad010","article-title":"Semaphorin 4C regulates ovarian steroidogenesis through RHOA\/ROCK1-mediated actin cytoskeleton rearrangement","volume":"29","author":"Chen","year":"2023","journal-title":"Mol. Hum. Reprod."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"103","DOI":"10.4149\/neo_2023_220206N139","article-title":"Semaphorin 3A inhibits tumor progression via the downregulation of Lin28B in ovarian cancer","volume":"70","author":"Ma","year":"2023","journal-title":"Neoplasma"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.3892\/ijmm.2015.2142","article-title":"Decreased semaphorin 3A expression is associated with a poor prognosis in patients with epithelial ovarian carcinoma","volume":"35","author":"Jiang","year":"2015","journal-title":"Int. J. Mol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1016\/j.fertnstert.2009.04.040","article-title":"The antral follicle count: Practical recommendations for better standardization","volume":"94","author":"Broekmans","year":"2010","journal-title":"Fertil. Steril."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1093\/humrep\/der092","article-title":"ESHRE consensus on the definition of \u2018poor response\u2019 to ovarian stimulation for in vitro fertilization: The Bologna criteria","volume":"26","author":"Ferraretti","year":"2011","journal-title":"Hum. Reprod."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ferretti, G., Romano, A., Sirabella, R., Serafini, S., Maier, T.J., and Matrone, C. (2022). An increase in Semaphorin 3A biases the axonal direction and induces an aberrant dendritic arborization in an in vitro model of human neural progenitor differentiation. Cell Biosci., 12.","DOI":"10.1186\/s13578-022-00916-1"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"206","DOI":"10.4103\/0974-1208.101023","article-title":"Anti-mullerian hormone cut-off values for predicting poor ovarian response to exogenous ovarian stimulation in in-vitro fertilization","volume":"5","author":"Satwik","year":"2012","journal-title":"J. Hum. Reprod. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1186\/s13048-021-00850-9","article-title":"Genetic determination of the ovarian reserve: A literature review","volume":"14","author":"Moiseeva","year":"2021","journal-title":"J. Ovarian. Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Hasegawa, Y., Kitahara, Y., Osuka, S., Tsukui, Y., Kobayashi, M., and Iwase, A. (2022). Effect of hypothyroidism and thyroid autoimmunity on the ovarian reserve: A systematic review and meta-analysis. Reprod. Med. Biol., 21.","DOI":"10.1002\/rmb2.12427"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2870","DOI":"10.1210\/en.2003-0043","article-title":"Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility","volume":"144","author":"Kao","year":"2003","journal-title":"Endocrinology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"bqac134","DOI":"10.1210\/endocr\/bqac134","article-title":"RhoB Promotes Endometrial Stromal Cells Decidualization Via Semaphorin3A\/PlexinA4 Signaling in Early Pregnancy","volume":"163","author":"Xu","year":"2022","journal-title":"Endocrinology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/j.cell.2018.12.009","article-title":"Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance","volume":"176","author":"Croizier","year":"2019","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"290","DOI":"10.3803\/EnM.2021.1343","article-title":"Developmental Hypothyroidism Influences the Development of the Entorhinal-Dentate Gyrus Pathway of Rat Offspring","volume":"37","author":"Jin","year":"2022","journal-title":"Endocrinol. Metab."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"209","DOI":"10.7150\/ijbs.5646","article-title":"Effects of hypothyroidism on expression of CRMP2B and ARPC5 during development of the rat frontal cortex","volume":"9","author":"Liu","year":"2013","journal-title":"Int. J. Biol. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Stallone, G., Matteo, M., Netti, G.S., Infante, B., Di Lorenzo, A., Prattichizzo, C., Carlucci, S., Trezza, F., Gesualdo, L., and Greco, P. (2017). Semaphorin 3F expression is reduced in pregnancy complicated by preeclampsia. An observational clinical study. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0174400"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.cca.2016.01.030","article-title":"Alteration of serum semaphorin 3B levels in preeclampsia","volume":"455","author":"Wang","year":"2016","journal-title":"Clin. Chim. Acta"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"101313","DOI":"10.1016\/j.tice.2019.101313","article-title":"Gene expression of four targets in situ of the first trimester maternal-fetoplacental interface","volume":"64","author":"Founds","year":"2020","journal-title":"Tissue Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1016\/j.placenta.2014.10.002","article-title":"Placental SEMA3B expression is not altered in severe early onset preeclampsia","volume":"35","author":"Hastie","year":"2014","journal-title":"Placenta"}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/14\/3\/358\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:10:47Z","timestamp":1760105447000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/14\/3\/358"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,8]]},"references-count":40,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["life14030358"],"URL":"https:\/\/doi.org\/10.3390\/life14030358","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,8]]}}}