{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T07:10:37Z","timestamp":1767337837883,"version":"build-2065373602"},"reference-count":63,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T00:00:00Z","timestamp":1666051200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Controlled ovarian hyperstimulation (COH) is essential for the success of in vitro fertilization (IVF). Evidence showing the comparison of different COH protocols remains predominantly of low certainty and derives from unspecified infertile and highly heterogeneous populations. Thus, personalized approaches to examine the response of patients to the various COH protocols need to be investigated. Data from in vitro and animal studies have identified the mechanistic target of rapamycin (mTOR) and Hippo signaling pathways play a key role in follicular homeostasis and oocyte quality. To be specific, current data indicate the controlled activation of mTOR and the controlled inhibition of the Hippo pathway within the ovarian granulosa cells (GC). Both are reported to lead to a nurturing follicular microenvironment, increase oocyte quality, and potentially improve reproductive outcomes. As intracellular markers, phosphorylated\/unphosphorylated levels of the pathways\u2019 main downstream mediators could be included among the candidate \u201cpersonalized\u201d predictors of patients\u2019 response to COH protocols and final IVF outcomes. Based on these hypotheses, we make a preliminary attempt to investigate their validity: We propose a prospective cohort study to compare the levels of certain phosphorylated\/unphosphorylated components of the investigated pathways (mTOR, ribosomal protein S6 kinase beta-1 (p70S6K-1), yes-associated protein-1 (YAP-1), and transcriptional coactivator with PDZ-binding motif (TAZ)) within the follicular fluid-isolated GC between women undergoing gonadotropin-releasing hormone (GnRH) antagonist\/\u201cshort\u201d protocols and those receiving GnRH agonist\/\u201clong 21\u201d protocols. A case-control design comparing these levels between women achieving pregnancy and those who did not is further planned. Additional analyses addressing the population\u2019s expected heterogeneity are planned after the completion of the pilot phase, during which 100 participants undergoing IVF are intended to be recruited. At this stage, these hypotheses are solely based on in vitro\/animal data, and thus, similar studies on humans in this respect are necessary for the investigation of their potential validity.<\/jats:p>","DOI":"10.3390\/jcm11206131","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T00:58:51Z","timestamp":1666141131000},"page":"6131","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Effect of Stimulation Protocols (GnRH Agonist vs. Antagonist) on the Activity of mTOR and Hippo Pathways of Ovarian Granulosa Cells and Its Potential Correlation with the Outcomes of In Vitro Fertilization: A Hypothesis"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8331-2402","authenticated-orcid":false,"given":"Michail","family":"Papapanou","sequence":"first","affiliation":[{"name":"Assisted Reproduction Unit, Second Department of Obstetrics and Gynecology, \u201cAretaieion\u201d Hospital, Medical School, National and Kapodistrian University of Athens, 76 Vas. Sofias Av., 11528 Athens, Greece"},{"name":"Second Department of Obstetrics and Gynecology, \u201cAretaieion\u201d Hospital, Medical School, National and Kapodistrian University of Athens, Vas. Sofias 76, 11528 Athens, Greece"},{"name":"Obstetrics, Gynecology and Reproductive Medicine Working Group, Society of Junior Doctors, 15123 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kalliopi","family":"Syristatidi","sequence":"additional","affiliation":[{"name":"School of Medicine, University of St. Andrews, North Haugh, St. Andrews KY16 9TF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3295-6811","authenticated-orcid":false,"given":"Maria","family":"Gazouli","sequence":"additional","affiliation":[{"name":"Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, 176 Michalakopoulou Str., 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4967-2505","authenticated-orcid":false,"given":"Makarios","family":"Eleftheriades","sequence":"additional","affiliation":[{"name":"Second Department of Obstetrics and Gynecology, \u201cAretaieion\u201d Hospital, Medical School, National and Kapodistrian University of Athens, Vas. Sofias 76, 11528 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikolaos","family":"Vlahos","sequence":"additional","affiliation":[{"name":"Assisted Reproduction Unit, Second Department of Obstetrics and Gynecology, \u201cAretaieion\u201d Hospital, Medical School, National and Kapodistrian University of Athens, 76 Vas. Sofias Av., 11528 Athens, Greece"},{"name":"Second Department of Obstetrics and Gynecology, \u201cAretaieion\u201d Hospital, Medical School, National and Kapodistrian University of Athens, Vas. Sofias 76, 11528 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0850-6623","authenticated-orcid":false,"given":"Charalampos","family":"Siristatidis","sequence":"additional","affiliation":[{"name":"Assisted Reproduction Unit, Second Department of Obstetrics and Gynecology, \u201cAretaieion\u201d Hospital, Medical School, National and Kapodistrian University of Athens, 76 Vas. Sofias Av., 11528 Athens, Greece"},{"name":"Second Department of Obstetrics and Gynecology, \u201cAretaieion\u201d Hospital, Medical School, National and Kapodistrian University of Athens, Vas. Sofias 76, 11528 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1093\/humrep\/der106","article-title":"Association between the number of eggs and live birth in IVF treatment: An analysis of 400 135 treatment cycles","volume":"26","author":"Sunkara","year":"2011","journal-title":"Hum. Reprod."},{"key":"ref_2","first-page":"CD012586","article-title":"Controlled ovarian stimulation protocols for assisted reproduction: A network meta-analysis","volume":"2017","author":"Gallos","year":"2017","journal-title":"Cochrane Database Syst. 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