title: Follicle-stimulating hormone potentiates the steroidogenic activity of chorionic gonadotropin and the anti-apoptotic activity of luteinizing hormone in human granulosa-lutein cells in vitro.
abstract: Luteinizing hormone (LH) and choriogonadotropin (hCG) are glycoprotein hormones regulating ovarian function and pregnancy, respectively. Since these molecules act on the same receptor (LHCGR), they were traditionally assumed as equivalent in assisted reproduction techniques (ART), although differences between LH and hCG were demonstrated at molecular and physiological level. In this study, we demonstrated for the first time that co-treatment with a follicle-stimulating hormone (FSH) dose in the ART therapeutic range potentiates different LH- and hCG-dependent responses in vitro, measured in terms of cAMP, phospho-CREB, -ERK1/2 and -AKT activation, gene expression, progesterone and estradiol production in human granulosa-lutein cells (hGLC). We show that in the presence of FSH, hCG biopotency is about 5-fold increased, in the presence of FSH, in terms of cAMP activation. Accordingly, CREB phosphorylation and steroid production is increased under hCG and FSH co-treatment. LH effects, evaluated as steroidogenic cAMP/PKA pathway activation, do not change in the presence of FSH, which, however, increases LH-dependent ERK1/2 and AKT, but not CREB phosphorylation, resulting in anti-apoptotic effects. The different modulatory activity of FSH on LH and hCG action in vitro corresponds to their different physiological functions, reflecting proliferative effects exerted by LH during the follicular phase and before trophoblast development, and the high steroidogenic potential of hCG requested to sustain pregnancy from the luteal phase onwards.
authors.affiliation: Unit of Endocrinology, Dept. Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy; Center for the Genomic Research, University of Modena and Reggio Emilia, Modena, Italy. Electronic address: livio.casarini@unimore.it.
authors.forename: Livio
authors.initials: L
authors.lastname: Casarini
authors.affiliation: Unit of Endocrinology, Dept. Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Riccetti
authors.affiliation: Unit of Endocrinology, Dept. Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: De Pascali
authors.affiliation: Unit of Obstetrics and Gynecology, IRCCS-Arcispedale Santa Maria Nuova, Reggio Emilia, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Nicoli
authors.affiliation: Dept. of Clinical Pathology, Azienda USL, Modena, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Tagliavini
authors.affiliation: Dept. of Clinical Pathology, Azienda USL, Modena, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Trenti
authors.affiliation: Unit of Obstetrics and Gynecology, IRCCS-Arcispedale Santa Maria Nuova, Reggio Emilia, Italy; Dept. of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Reggio Emilia, Italy.
authors.forename: Giovanni Battista
authors.initials: GB
authors.lastname: La Sala
authors.affiliation: Unit of Endocrinology, Dept. Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy; Center for the Genomic Research, University of Modena and Reggio Emilia, Modena, Italy; Dept. of Medicine, Endocrinology, Metabolism and Geriatrics, Azienda USL, Modena, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Simoni
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008184:Luteal Cells / Q000166:cytology / Q000187:drug effects*; D007986:Luteinizing Hormone / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013256:Steroids / Q000378:metabolism*
chemical_list: C115163:CREB1 protein, human; D006063:Chorionic Gonadotropin; D017362:Cyclic AMP Response Element-Binding Protein; D013256:Steroids; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D000242:Cyclic AMP
keywords: FSH; Granulosa cells; LH; LHCGR; hCG