title: Everolimus, an mTOR pathway inhibitor, is highly successful on ovarian hyperstimulation syndrome by reducing ovarian weight and progesterone levels: a preclinical experimental randomized controlled study.
abstract: The usefulness of various pathways inhibitors, Everolimus, an inhibitor of mammalian target of rapamycin (mTOR), Infliximab, a monoclonal antibody which blocks the tumor necrosis factor-a (TNF-a), Erlotinib, a tyrosine protein kinase inhibitor of the epidermal growth factor receptor (EGFR), Metformin, an activator of AMP-activated protein kinase enzyme (AMPK) and vascular permeability reducers were explored in an ovarian hyperstimulation syndrome (OHSS) rat model. Sixty-three female Wistar rats were randomly divided in seven groups. The control group received saline, while the OHSS group received recombinant -- follicle-stimulating hormone (rec-FSH) for four consecutive days. The other five groups received rec-FSH for 4 d and Everolimus daily, Infliximab once, Erlotinib daily, Metformin daily and Vitamin C daily, respectively. All groups received human chorionic gonadotropin (hCG) at the fifth day. The efficacy of Everolimus administration for various intervals was also explored. Significantly reduced ovarian weight was observed in the Everolimus group (rec-FSH + hCG + mTOR inhibitor) compared to the OHSS group (p < 0.001). The Everolimus group also showed the lowest progesterone (PRG) concentration (p = 0.007). The Erlotinib group (rec-FSH + hCG + EGFR inhibitor) presented with the lowest graafian follicle number, while the Everolimus group was characterized by the lowest corpus luteum number. The vascular permeability and the estradiol levels did not differ between groups. Finally, the Everolimus intra-comparison showed no difference in all measured outcomes. Studying the different pathways linked to vascular endothelial growth factor (VEGF) pathway, we conclude that targeting mTOR pathways is beneficial for reducing ovarian weight and PRG levels in an OHSS animal model.
authors.affiliation: a Department of Obstetrics and Gynecology , Ioannina State General Hospital G. Chatzikosta , Ioannina , Greece .|b The International Translational Medicine and Biomodeling Research Team, MIPT Center for Human Physiology Studies, Laboratory of Cellular and Molecular Technologies, Moscow Institute of Physics and Technology , Moscow , Russia .
authors.forename: Ioannis P
authors.initials: IP
authors.lastname: Kosmas
authors.affiliation: c Genetics and IVF Unit, Department of Obstetrics and Gynecology , Medical School, Ioannina University , Ioannina , Greece .
authors.forename: Chrysoula
authors.initials: C
authors.lastname: Kitsou
authors.affiliation: c Genetics and IVF Unit, Department of Obstetrics and Gynecology , Medical School, Ioannina University , Ioannina , Greece .
authors.forename: Leandros
authors.initials: L
authors.lastname: Lazaros
authors.affiliation: d Department of Neurology , Medical School, Ioannina University , Ioannina , Greece .
authors.forename: Sofia
authors.initials: S
authors.lastname: Markoula
authors.affiliation: e Laboratory of Physiology , Medical School, Ioannina University , Ioannina , Greece .
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Peschos
authors.affiliation: b The International Translational Medicine and Biomodeling Research Team, MIPT Center for Human Physiology Studies, Laboratory of Cellular and Molecular Technologies, Moscow Institute of Physics and Technology , Moscow , Russia .
authors.forename: Ospan
authors.initials: O
authors.lastname: Mynbaev
authors.affiliation: f Vrije Universiteit Brussel and Centre for Reproductive Medicine , Brussels , Belgium .
authors.forename: Herman
authors.initials: H
authors.lastname: Tournaye
authors.affiliation: g Iakentro IVF Center , Thessaloniki , Greece and.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Prapas
authors.affiliation: g Iakentro IVF Center , Thessaloniki , Greece and.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Prapas
authors.affiliation: c Genetics and IVF Unit, Department of Obstetrics and Gynecology , Medical School, Ioannina University , Ioannina , Greece .
authors.forename: Athanasios
authors.initials: A
authors.lastname: Zikopoulos
authors.affiliation: h Department of Anatomy-Histology-Embryology , Medical School, Ioannina University , Ioannina , Greece.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Galani
authors.affiliation: c Genetics and IVF Unit, Department of Obstetrics and Gynecology , Medical School, Ioannina University , Ioannina , Greece .
authors.forename: Ioannis
authors.initials: I
authors.lastname: Georgiou
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D006063:Chorionic Gonadotropin / Q000009:adverse effects; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use; D000068338:Everolimus / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005640:Follicle Stimulating Hormone / Q000009:adverse effects; D006728:Hormones / Q000009:adverse effects; D000069285:Infliximab / Q000494:pharmacology / Q000627:therapeutic use; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use; D009929:Organ Size; D016471:Ovarian Hyperstimulation Syndrome / Q000139:chemically induced / Q000188:drug therapy*; D010053:Ovary / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011374:Progesterone / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012102:Reproductive Control Agents / Q000009:adverse effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D006063:Chorionic Gonadotropin; D006728:Hormones; D047428:Protein Kinase Inhibitors; D012102:Reproductive Control Agents; D014409:Tumor Necrosis Factor-alpha; D011374:Progesterone; D005640:Follicle Stimulating Hormone; D008687:Metformin; D000068338:Everolimus; D000069285:Infliximab; D000069347:Erlotinib Hydrochloride; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: mTOR inhibition; ovarian hyperstimulation; ovarian weight; progesterone; rat model