Oral follicle stimulating hormone (FSH) receptor agonist affects granulosa cells differently than recombinant human FSH.

To determine whether TOP5300, a novel oral follicle stimulating hormone receptor (FSHR) allosteric agonist, elicits a different cellular response than recombinant human FSH (rh-FSH) in human granulosa cells from in vitro fertilization patients.Basic science research with a preclinical allosteric FSHR agonist.Infertility patients at a single academic fertility clinic were recruited under an IRB-approved protocol. Primary granulosa cell cultures were established for 41 patients, of which 8 had normal ovarian reserve (NOR), 17 were of advanced reproductive age (ARA), 12 had a diagnosis of polycystic ovarian syndrome (PCOS), and 4 had a combination of diagnoses, such as ARA and PCOS.Primary granulosa-lutein cell (GLC) cultures were treated with rh-FSH, TOP5300 or vehicle.Estradiol production by ELISA, steroid pathway gene expression of StAR and aromatase by quantitative polymerase chain reaction, and FSH receptor membrane localization by immunofluorescence were measured in human GLC.TOP5300 consistently stimulated estradiol production among NOR, ARA and PCOS patients. Recombinant FSH was the more potent ligand in GLC from NOR patients but was ineffective in cells from ARA or PCOS patients. The lowest level of FSHR plasma membrane localization was seen in patients with ARA (p<0.0001) while FSHR localization was more abundant in cells from PCOS patients (p = 0.0299); the highest levels were present in cells from NOR patients. Localization of FSHR was not affected by TOP5300 relative to rh-FSH among any patient group. TOP5300 stimulated greater expression of StAR (p=0.008) and CYP19A1 (p=0.006) across cells from all patients (NOR, ARA and PCOS combined), while rh-FSH was unable to stimulate StAR and aromatase (CYP19A1) expression in cells from PCOS patients. TOP5300-induced expression of StAR and CYP19A1 mRNA among ARA and NOR patients were consistently lower than those observed in cells from PCOS patients.TOP5300 appears to stimulate estradiol production and steroidogenic gene expression from GLC more than rh-FSH in PCOS, relative to ARA and NOR, patients. It does not appear that localization of FSHR at cell membranes is a limiting step for TOP5300 or rh-FSH stimulation of steroidogenic gene expression and estradiol production.Copyright © 2023. Published by Elsevier Inc.

Citation

Joie Z Guner, Diana Monsivais, Henry Yu, Fabio Stossi, Hannah L Johnson, William E Gibbons, Martin M Matzuk, Stephen Palmer. Oral follicle stimulating hormone (FSH) receptor agonist affects granulosa cells differently than recombinant human FSH. Fertility and sterility. 2023 Jul 31

PMID: 37532169

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