{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T22:25:43Z","timestamp":1786487143359,"version":"build-2736575974"},"reference-count":72,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T00:00:00Z","timestamp":1761868800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["22-74-10009"],"award-info":[{"award-number":["22-74-10009"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Government Program for Basic Research in the Koltzov Institute of Developmental Biology of the Russian Academy of Sciences in 2025","award":["0088-2024-0012"],"award-info":[{"award-number":["0088-2024-0012"]}]},{"name":"Development Program of the MSU Interdisciplinary Scientific and Educational School \u201cMolecular technologies of living systems and synthetic biology\u201d at Lomonosov Moscow State University","award":["23-SH04-20"],"award-info":[{"award-number":["23-SH04-20"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed, yet their direct impact on ovarian function remains poorly understood. While serotonin signaling is known to occur within the ovarian follicle, the specific molecular consequences of its disruption by SSRIs are unclear. This study aimed to elucidate the direct, intra-ovarian mechanisms by which fluoxetine, a common SSRI, affects follicular development and oocyte competence. Methods: We administered fluoxetine (20 mg\/kg) or vehicle daily for seven days to both prepubertal and adult female mice to model short-term therapeutic exposure. Results: Fluoxetine treatment successfully blocked peripheral serotonin uptake, reducing serum levels by over 90%. Crucially, this occurred without altering circulating levels of estradiol, FSH, or LH and without disrupting the estrous cycle, indicating a mechanism independent of the central hypothalamic\u2013pituitary\u2013gonadal axis. Instead, we pinpoint a direct ovarian effect: fluoxetine inhibited serotonin transport activity in oocytes and significantly downregulated the expression of the pivotal oocyte-derived growth factor Gdf9. This was accompanied by reduced expression of genes crucial for granulosa cell function (Lhr, Fshr) and steroidogenesis (Cyp19a1). Functionally, these molecular changes manifested as a decline in oocyte quality and a significant reduction in ovulation rates in adult mice. Notably, these detrimental effects were more pronounced in prepubertal mice, indicating a heightened vulnerability during early follicular development. Conclusions: Our findings reveal a direct, intra-ovarian mechanism of fluoxetine-induced disruption. By inhibiting oocyte serotonin transport and downregulating GDF9, fluoxetine impairs critical oocyte\u2013granulosa cell communication, thereby compromising oocyte competence and reducing fertility outcomes. This work identifies follicular development as a critical window of susceptibility to SSRI exposure, holding significant clinical implications for reproductive-aged and adolescent populations.<\/jats:p>","DOI":"10.3390\/ph18111647","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T13:47:58Z","timestamp":1762177678000},"page":"1647","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Fluoxetine Disrupts Ovarian Serotonin Signaling and Oocyte Competence in Mice"],"prefix":"10.3390","volume":"18","author":[{"given":"Nina M.","family":"Alyoshina","sequence":"first","affiliation":[{"name":"Koltzov Institute of Developmental Biology, 26 Vavilov Street, Moscow 119334, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9606-8833","authenticated-orcid":false,"given":"Maria V.","family":"Beketova","sequence":"additional","affiliation":[{"name":"Koltzov Institute of Developmental Biology, 26 Vavilov Street, Moscow 119334, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1475-0981","authenticated-orcid":false,"given":"Maria D.","family":"Tkachenko","sequence":"additional","affiliation":[{"name":"Koltzov Institute of Developmental Biology, 26 Vavilov Street, Moscow 119334, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulia O.","family":"Nikishina","sequence":"additional","affiliation":[{"name":"Koltzov Institute of Developmental Biology, 26 Vavilov Street, Moscow 119334, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8401-3367","authenticated-orcid":false,"given":"Veronika S.","family":"Frolova","sequence":"additional","affiliation":[{"name":"Department of Embryology, Biological Faculty, Lomonosov Moscow State University, Lenin Hills, 1\/12, Moscow 119234, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyudmila A.","family":"Malchenko","sequence":"additional","affiliation":[{"name":"Koltzov Institute of Developmental Biology, 26 Vavilov Street, Moscow 119334, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria L.","family":"Semenova","sequence":"additional","affiliation":[{"name":"Department of Embryology, Biological Faculty, Lomonosov Moscow State University, Lenin Hills, 1\/12, Moscow 119234, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria P.","family":"Rubtsova","sequence":"additional","affiliation":[{"name":"Department of Chemistry of Natural Compounds, Faculty of Chemistry, Lomonosov Moscow State University, Lenin Hills, 1\/3, Moscow 119234, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9238-9206","authenticated-orcid":false,"given":"Denis A.","family":"Nikishin","sequence":"additional","affiliation":[{"name":"Koltzov Institute of Developmental Biology, 26 Vavilov Street, Moscow 119334, Russia"},{"name":"Department of Embryology, Biological Faculty, Lomonosov Moscow State University, Lenin Hills, 1\/12, Moscow 119234, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1503\/jpn.150205","article-title":"Why Is Depression More Prevalent in Women?","volume":"40","author":"Albert","year":"2015","journal-title":"J. Psychiatry Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Kaihola, H., Yaldir, F.G., Hreinsson, J., H\u00f6rnaeus, K., Bergquist, J., Olivier, J.D.A., \u00c5kerud, H., and Sundstr\u00f6m-Poromaa, I. (2016). Effects of Fluoxetine on Human Embryo Development. Front. Cell. Neurosci., 10.","DOI":"10.3389\/fncel.2016.00160"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.taap.2012.09.020","article-title":"Dual Effects of Fluoxetine on Mouse Early Embryonic Development","volume":"265","author":"Kim","year":"2012","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.reprotox.2015.12.006","article-title":"Inhibition of Serotonin Reuptake in the Prepubertal Rat Ovary by Fluoxetine and Effects on Ovarian Functions","volume":"59","author":"Ayala","year":"2016","journal-title":"Reprod. Toxicol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"h3190","DOI":"10.1136\/bmj.h3190","article-title":"Specific SSRIs and Birth Defects: Bayesian Analysis to Interpret New Data in the Context of Previous Reports","volume":"351","author":"Reefhuis","year":"2015","journal-title":"BMJ"},{"key":"ref_6","first-page":"1","article-title":"Effects of Selective Serotonin Reuptake Inhibitors on Endocrine System (Review)","volume":"21","year":"2024","journal-title":"Biomed. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"G\u00f6k, S., G\u00f6k, B.C., Alata\u015f, E., Senol, H., and Topak, O.Z. (2023). Effects of Selective Serotonin Reuptake Inhibitor Treatment on Ovarian Reserves in Patients with Depression. Medicina, 59.","DOI":"10.3390\/medicina59030517"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Feng, Y., Qu, X., and Hao, H. (2025). Progress in the Study of the Effects of Selective Serotonin Reuptake Inhibitors (SSRIs) on the Reproductive System. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1567863"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1177\/026988119801200201","article-title":"The Serotonin Transporter: A Primary Target for Antidepressant Drugs","volume":"12","author":"Schloss","year":"1998","journal-title":"J. Psychopharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1146\/annurev.med.60.042307.110802","article-title":"The Expanded Biology of Serotonin","volume":"60","author":"Berger","year":"2009","journal-title":"Annu. Rev. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1016\/j.febslet.2015.05.054","article-title":"The Roles of Peripheral Serotonin in Metabolic Homeostasis","volume":"589","author":"Mayer","year":"2015","journal-title":"FEBS Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1016\/j.lfs.2007.09.034","article-title":"Local Serotonergic Signaling in Mammalian Follicles, Oocytes and Early Embryos","volume":"81","author":"Amireault","year":"2007","journal-title":"Life Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1002\/jcp.20170","article-title":"A Serotonin Receptor Antagonist Induces Oocyte Maturation in Both Frogs and Mice: Evidence That the Same G Protein Ptor Is Responsible for Maintaining Meiosis Arrest in Both Species","volume":"202","author":"Sheng","year":"2005","journal-title":"J. Cell. Physiol."},{"key":"ref_14","first-page":"030006051987933","article-title":"Serum and Follicular Fluid Levels of Serotonin, Kisspeptin, and Brain-Derived Neurotrophic Factor in Patients Undergoing in Vitro Fertilization: An Observational Study","volume":"48","author":"Sulyok","year":"2020","journal-title":"J. Int. Med. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1017\/S0967199404002862","article-title":"Serotonin Localization and Its Functional Significance during Mouse Preimplantation Embryo Development","volume":"12","author":"Cikos","year":"2004","journal-title":"Zygote"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1530\/REP-07-0577","article-title":"Serotonin in Pre-Implantation Mouse Embryos Is Localized to the Mitochondria and Can Modulate Mitochondrial Potential","volume":"135","author":"Basu","year":"2008","journal-title":"Reproduction"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Nikishin, D.A., Alyoshina, N.M., Semenova, M.L., and Shmukler, Y.B. (2019). Analysis of Expression and Functional Activity of Aromatic L-Amino Acid Decarboxylase (DDC) and Serotonin Transporter (SERT) as Potential Sources of Serotonin in Mouse Ovary. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20123070"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Alyoshina, N.M., Tkachenko, M.D., Malchenko, L.A., Shmukler, Y.B., and Nikishin, D.A. (2022). Uptake and Metabolization of Serotonin by Granulosa Cells Form a Functional Barrier in the Mouse Ovary. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232314828"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1134\/S1062360421020065","article-title":"Oocyte-Mediated Effect of Serotonin on the Functional Status of Granulosa Cells","volume":"52","author":"Nikishin","year":"2021","journal-title":"Russ. J. Dev. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"33","DOI":"10.23868\/201707027","article-title":"Expression Dynamics of the Serotonergic System Components in Granulosa Cells of the Developing Ovarian Follicle and after Luteinization","volume":"XII","author":"Nikishin","year":"2017","journal-title":"Genes Cells"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"S59","DOI":"10.1134\/S1990747823060041","article-title":"Spatial Organization of the Components of the Serotonergic System in the Early Mouse Development","volume":"17","author":"Frolova","year":"2023","journal-title":"Biochem. (Moscow) Suppl. Ser. A Membr. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1038\/s41598-017-01291-5","article-title":"Serotonin Transporter Deficiency Drives Estrogen-Dependent Obesity and Glucose Intolerance","volume":"7","author":"Zha","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1124\/jpet.118.255380","article-title":"Effect of Pregnancy on Paroxetine-Induced Adiposity and Glucose Intolerance in Mice","volume":"371","author":"Zha","year":"2019","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.mce.2016.11.021","article-title":"Fluoxetine and Its Active Metabolite Norfluoxetine Disrupt Estrogen Synthesis in a Co-Culture Model of the Feto-Placental Unit","volume":"442","author":"Laurent","year":"2017","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1677\/joe.0.1250433","article-title":"Serotonin Enhances Oestradiol Production by Hamster Preovulatory Follicles in Vitro: Effects of Experimentally Induced Atresia","volume":"125","author":"Terranova","year":"1990","journal-title":"J. Endocrinol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/0024-3205(93)90713-D","article-title":"Serotonin Stimulates Steroidogenesis in Rat Preovulatory Follicles: Involvement of 5-HT2 Receptor","volume":"53","author":"Tanaka","year":"1993","journal-title":"Life Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1385\/ENDO:24:2:155","article-title":"Serotonin May Alter the Pattern of Gonadotropin-Induced Progesterone Release of Human Granulosa Cells in Superfusion System","volume":"24","author":"Koppan","year":"2004","journal-title":"Endocrine"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.jad.2019.02.063","article-title":"Plasma Serotonin Levels Are Associated with Antidepressant Response to SSRIs","volume":"250","author":"Holck","year":"2019","journal-title":"J. Affect. Disord."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1053\/cp.1999.v66.103402001","article-title":"Decreased Platelet Serotonin Transporter Sites and Increased Platelet Inositol Triphosphate Levels in Patients with Unipolar Depression: Effects of Clomipramine and Fluoxetine","volume":"66","author":"Alvarez","year":"1999","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Alyoshina, N.M., Tkachenko, M.D., Nikishina, Y.O., Nikishin, D.A., and Koltzov, N.K. (2023). Serotonin Transporter Activity in Mouse Oocytes Is a Positive Indicator of Follicular Growth and Oocyte Maturity. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241411247"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Tkachenko, M.D., Alyoshina, N.M., Nikishina, Y.O., Frolova, V.S., and Nikishin, D.A. (2025). Impact of Chronic Fluoxetine Exposure on Oocyte Development and Reproductive Outcomes in a Mouse Model. Int. J. Mol. Sci., 26.","DOI":"10.20944\/preprints202504.1734.v1"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Chen, Y., Liu, Q., Liu, R., Yang, C., Wang, X., Ran, Z., Zhou, S., Li, X., and He, C. (2021). A Prepubertal Mice Model to Study the Growth Pattern of Early Ovarian Follicles. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22105130"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1093\/biolre\/ioad095","article-title":"Mouse Primary Follicles Experience Slow Growth Rates after Activation and Progressive Increases That Influence the Duration of the Primary Follicle Phase","volume":"109","author":"Richard","year":"2023","journal-title":"Biol. Reprod."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1093\/molehr\/gau007","article-title":"The Two Classes of Primordial Follicles in the Mouse Ovary: Their Development, Physiological Functions and Implications for Future Research","volume":"20","author":"Zheng","year":"2014","journal-title":"Mol. Hum. Reprod."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1093\/biolre\/ioad134","article-title":"Ovarian Follicle Size or Growth Rate Can Both Be Determinants of Ovulatory Follicle Selection in Mice","volume":"110","author":"Richard","year":"2024","journal-title":"Biol. Reprod."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1038\/sj.npp.1300433","article-title":"Effects of Chronic Fluoxetine in Animal Models of Anxiety and Depression","volume":"29","author":"Dulawa","year":"2004","journal-title":"Neuropsychopharmacology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1177\/0004563219880567","article-title":"Use of Selective Serotonin Reuptake Inhibitors Is Associated with Very Low Plasma-Free Serotonin Concentrations in Humans","volume":"57","author":"Peters","year":"2020","journal-title":"Ann. Clin. Biochem. Int. J. Lab. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/S0192-0561(99)00035-1","article-title":"[3H]Paroxetine Binding to Human Peripheral Lymphocyte Membranes of Patients with Major Depression before and after Treatment with Fluoxetine","volume":"21","author":"Urbina","year":"1999","journal-title":"Int. J. Immunopharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1038\/npp.2009.47","article-title":"Paradoxical Anxiogenic Response of Juvenile Mice to Fluoxetine","volume":"34","author":"Oh","year":"2009","journal-title":"Neuropsychopharmacology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e028201","DOI":"10.1136\/bmjopen-2018-028201","article-title":"What Were the Impacts of the Committee on Safety of Medicines Warning and Publication of the NICE Guidelines on Trends in Child and Adolescent Antidepressant Prescribing in Primary Care? A Population Based Study","volume":"9","author":"Tiffin","year":"2019","journal-title":"BMJ Open"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.cccn.2004.12.019","article-title":"Western Blot Analysis of Human and Rat Serotonin Transporter in Platelets and Brain Using Site-Specific Antibodies: Evidence That Transporter Undergoes Endoproteolytic Cleavage","volume":"356","author":"Dmitriev","year":"2005","journal-title":"Clin. Chim. Acta"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2416","DOI":"10.1098\/rstb.2011.0361","article-title":"Effects of the Antidepressant Fluoxetine on the Subcellular Localization of 5-HT 1A Receptors and SERT","volume":"367","author":"Descarries","year":"2012","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1126\/science.285.5428.763","article-title":"Phosphorylation and Sequestration of Serotonin Transporters Differentially Modulated by Psychostimulants","volume":"285","author":"Ramamoorthy","year":"1999","journal-title":"Science"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"9635","DOI":"10.1523\/JNEUROSCI.0440-09.2009","article-title":"Fluoxetine (Prozac) Binding to Serotonin Transporter Is Modulated by Chloride and Conformational Changes","volume":"29","author":"Tavoulari","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1007\/s10815-018-1268-4","article-title":"GDF-9 and BMP-15 Direct the Follicle Symphony","volume":"35","author":"Sanfins","year":"2018","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1071\/RD14099","article-title":"Signalling Pathways Involved in the Synergistic Effects of Human Growth Differentiation Factor 9 and Bone Morphogenetic Protein 15","volume":"28","author":"Reader","year":"2016","journal-title":"Reprod. Fertil. Dev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1002\/mrd.21265","article-title":"Integral Role of GDF-9 and BMP-15 in Ovarian Function","volume":"78","author":"Otsuka","year":"2011","journal-title":"Mol. Reprod. Dev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2456","DOI":"10.1210\/me.2005-0357","article-title":"Growth Differentiation Factor 9 Is Antiapoptotic during Follicular Development from Preantral to Early Antral Stage","volume":"20","author":"Orisaka","year":"2006","journal-title":"Mol. Endocrinol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1095\/biolreprod.104.033357","article-title":"RNA Interference Evidence That Growth Differentiation Factor-9 Mediates Oocyte Regulation of Cumulus Expansion in Mice","volume":"72","author":"Gui","year":"2005","journal-title":"Biol. Reprod."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"32889","DOI":"10.1074\/jbc.M103212200","article-title":"Biological Function and Cellular Mechanism of Bone Morphogenetic Protein-6 in the Ovary","volume":"276","author":"Otsuka","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2926","DOI":"10.1210\/en.2018-00189","article-title":"BMP6 Downregulates GDNF Expression through SMAD1\/5 and ERK1\/2 Signaling Pathways in Human Granulosa-Lutein Cells","volume":"159","author":"Zhang","year":"2018","journal-title":"Endocrinology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.3892\/etm.2017.4603","article-title":"Increased Bone Morphogenetic Protein-6 in Follicular Fluidand Granulosa Cells May Correlate with Fertilization and Embryo Quality in Humans","volume":"14","author":"Liang","year":"2017","journal-title":"Exp. Ther. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"35747","DOI":"10.1074\/jbc.M604008200","article-title":"Characterization of NOBOX DNA Binding Specificity and Its Regulation of Gdf9 and Pou5f1 Promoters","volume":"281","author":"Choi","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.steroids.2011.10.013","article-title":"Tissue Physiology and Pathology of Aromatase","volume":"77","author":"Stocco","year":"2012","journal-title":"Steroids"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"173998","DOI":"10.1016\/j.ejphar.2021.173998","article-title":"Antidepressants\u2019 Effects on Testosterone and Estrogens: What Do We Know?","volume":"899","author":"Pavlidi","year":"2021","journal-title":"Eur. J. Pharmacol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"100743","DOI":"10.1016\/j.animal.2023.100743","article-title":"Review: Roles of Follicle-Stimulating Hormone in Preantral Folliculogenesis of Domestic Animals: What Can We Learn from Model Species and Where Do We Go from Here?","volume":"17","author":"Morton","year":"2023","journal-title":"Animal"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1186\/s13048-021-00880-3","article-title":"An Overview of FSH-FSHR Biology and Explaining the Existing Conundrums","volume":"14","author":"Bhartiya","year":"2021","journal-title":"J. Ovarian Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/1477-7827-8-11","article-title":"Differential Genome-Wide Gene Expression Profiling of Bovine Largest and Second-Largest Follicles: Identification of Genes Associated with Growth of Dominant Follicles","volume":"8","author":"Hayashi","year":"2010","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1093\/humupd\/dml062","article-title":"Molecular Mechanisms of Ovulation: Co-Ordination through the Cumulus Complex","volume":"13","author":"Russell","year":"2007","journal-title":"Hum. Reprod. Update"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.ydbio.2006.07.012","article-title":"The Preantral Granulosa Cell to Cumulus Cell Transition in the Mouse Ovary: Development of Competence to Undergo Expansion","volume":"299","author":"Diaz","year":"2006","journal-title":"Dev. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1530\/REP-09-0144","article-title":"Cumulus Gene Expression as a Predictor of Human Oocyte Fertilisation, Embryo Development and Competence to Establish a Pregnancy","volume":"138","author":"Anderson","year":"2009","journal-title":"Reproduction"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1210\/mend.13.6.0310","article-title":"Paracrine Actions Of Growth Differentiation Factor-9 in the Mammalian Ovary","volume":"13","author":"Elvin","year":"1999","journal-title":"Mol. Endocrinol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1017\/S0967199402002101","article-title":"The Analysis of Chromatin Organisation Allows Selection of Mouse Antral Oocytes Competent for Development to Blastocyst","volume":"10","author":"Zuccotti","year":"2002","journal-title":"Zygote"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1928","DOI":"10.4161\/cc.24991","article-title":"Maternal Factors Required for Oocyte Developmental Competence in Mice: Transcriptome Analysis of Non-Surrounded Nucleolus (NSN) and Surrounded Nucleolus (SN) Oocytes","volume":"12","author":"Ma","year":"2013","journal-title":"Cell Cycle"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.phrs.2016.05.031","article-title":"Are Fluoxetine\u2019s Effects Due to Sigma-1 Receptor Agonism?","volume":"113","author":"Safrany","year":"2016","journal-title":"Pharmacol. Res."},{"key":"ref_66","first-page":"e4389","article-title":"Performing Vaginal Lavage, Crystal Violet Staining, and Vaginal Cytological Evaluation for Mouse Estrous Cycle Staging Identification","volume":"67","author":"McLean","year":"2012","journal-title":"J. Vis. Exp."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"99","DOI":"10.32607\/20758251-2019-11-4-99-103","article-title":"Tear Fluid Catecholamines as Biomarkers of the Parkinson\u2019s Disease: A Clinical and Experimental Study","volume":"11","author":"Kim","year":"2019","journal-title":"Acta Naturae"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1134\/S1062360423030025","article-title":"Analysis of the Ovarian Marker Genes Expression Revealed the Antagonistic Effects of Serotonin and Androstenedione on the Functional State of Mouse Granulosa Cells in Primary Culture","volume":"54","author":"Alyoshina","year":"2023","journal-title":"Russ. J. Dev. Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1017\/S0967199419000492","article-title":"Reference Genes Selection for Real-Time Quantitative PCR Analysis in Mouse Germinal Vesicle Oocytes","volume":"27","author":"Filatov","year":"2019","journal-title":"Zygote"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1007\/s10815-018-1263-9","article-title":"Selection of Stable Expressed Reference Genes in Native and Vitrified\/Thawed Human Ovarian Tissue for Analysis by QRT-PCR and Western Blot","volume":"35","author":"Nikishin","year":"2018","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"807","DOI":"10.2144\/000112761","article-title":"A Quantitative Real-Time PCR Method for Absolute Telomere Length","volume":"44","author":"Dhillon","year":"2008","journal-title":"Biotechniques"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2527","DOI":"10.1038\/s41467-025-57794-7","article-title":"Telomere Length in Offspring Is Determined by Mitochondrial-Nuclear Communication at Fertilization","volume":"16","author":"Winstanley","year":"2025","journal-title":"Nat. Commun."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/11\/1647\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T14:04:19Z","timestamp":1762178659000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/11\/1647"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,31]]},"references-count":72,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ph18111647"],"URL":"https:\/\/doi.org\/10.3390\/ph18111647","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,31]]}}}