AUTHOR=Bøtkjær Jane Alrø , Kristensen Stine Gry , Olesen Hanna Ørnes , Larsson Per , Mannaerts Bernadette , Andersen Claus Yding 

TITLE=Dose-dependent stimulation of human follicular steroidogenesis by a novel rhCG during ovarian stimulation with fixed rFSH dosing

JOURNAL=Frontiers in Endocrinology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.1004596

DOI=10.3389/fendo.2022.1004596

ISSN=1664-2392

ABSTRACT=<sec><title>Background</title><p>Choriogonadotropin (CG) beta (FE 999302), a novel recombinant human (h)CG produced by a human cell line, has a longer half-life and higher potency than CG alfa produced by a Chinese hamster ovary cell line. hCG augments steroid production, but the extent of which CG beta treatment during ovarian stimulation (OS) increases steroidogenesis is unknown.</p></sec><sec><title>Objective</title><p>To explore how increasing doses of CG beta during OS augment follicular steroidogenesis and change gene expression in cumulus cells.</p></sec><sec><title>Study design</title><p>This study is part of a randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of CG beta plus recombinant follicle-stimulating hormone (rFSH) in women undergoing OS during a long gonadotrophin-releasing hormone agonist protocol. The study primary endpoint was intrafollicular steroid concentrations after CG beta administration. Secondary outcomes were gene expression of <italic><italic>FSHR</italic></italic>, <italic>LHR</italic>, <italic>CYP19a1</italic>, and <italic>androgen receptor</italic> (<italic>AR</italic>).</p></sec><sec><title>Participants/methods</title><p>619 women with anti-Müllerian hormone levels 5–35 pmol/L were randomized to receive placebo or 1, 2, 4, 8, or 12 µg/day CG beta from Day 1 of OS plus rFSH. Follicular fluid (FF) (n=558), granulosa (n=498) and cumulus cells (n=368) were collected at oocyte retrieval. Steroid FF hormones were measured using enzyme-linked immunosorbent assays, gene expression was analyzed in cumulus cells by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and single nucleotide polymorphism (SNP) analysis was performed in granulosa cells.</p></sec><sec><title>Results</title><p>17-OH-progesterone, androstenedione, testosterone, and estradiol concentrations significantly increased in a CG-beta dose-dependent manner during OS (p&lt;0.0001), reaching up to 10 times higher values in the highest dose group versus placebo. There was no difference between CG beta dose groups and placebo for progesterone. Expression levels of <italic>CYP19a1</italic> increased significantly in the highest dose group of CG beta (p=0.0325) but levels of <italic><italic>FSHR</italic></italic>, <italic>LHR</italic> and <italic>AR</italic> were not affected by CG beta administration. There were no differences between the <italic><italic>FSHR</italic></italic>(307) or <italic>LHR</italic>(312) SNP genotypes for dose-dependent effects of CG beta in relation to number of oocytes, intrafollicular steroid hormone levels, or gene expression levels.</p></sec><sec><title>Conclusions</title><p>These results reflect the importance of the combined effect of FSH and hCG/LH during OS on granulosa cell activity, follicle health and potentially oocyte quality.</p></sec><sec><title>Trial Registration number</title><p>2017-003810-13 (EudraCT Number).</p></sec><sec><title>Trial Registration date</title><p>21 May 2018.</p></sec><sec><title>Date of first patient’s enrolment</title><p>13 June 2018. Presented at the 38th Annual Meeting of the European Society of Human Reproduction and Embryology, P-567, 2022.</p></sec>