Dose-dependent stimulation of human follicular steroidogenesis by a novel rhCG during ovarian stimulation with fixed
Jane Alrø Bøtkjær1, Stine Gry Kristensen1, Hanna Ørnes Olesen1
1Laboratory of Reproductive Biology, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark.
Background:
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.
Objective:
To explore how increasing doses of CG beta during OS augment follicular steroidogenesis and change gene expression in cumulus cells.
Study Design:
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 FSHR , LHR, CYP19a1, and androgen receptor (AR).
Participants/Methods:
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.
Results:
17-OH-progesterone, androstenedione, testosterone, and estradiol concentrations significantly increased in a CG-beta dose-dependent manner during OS (p<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 CYP19a1 increased significantly in the highest dose group of CG beta (p=0.0325) but levels of FSHR , LHR and AR were not affected by CG beta administration. There were no differences between the FSHR (307) or LHR(312) SNP genotypes for dose-dependent effects of CG beta in relation to number of oocytes, intrafollicular steroid hormone levels, or gene expression levels.
Conclusions:
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.
Trial Registration Number:
2017-003810-13 (EudraCT Number).
Trial Registration Date:
21 May 2018.
Date Of First Patient’S Enrolment:
13 June 2018. Presented at the 38th Annual Meeting of the European Society of Human Reproduction and Embryology, P-567, 2022.
Related Concept Videos
01:30Hormonal Control of the Ovarian Cycle
Before puberty, the hypothalamus releases GnRH in a low frequency, low amplitude pulsatile manner. This along with the immature hypothalamic-pituitary-gonadal axis activity, results in low estrogen levels and the absence of a fully functional ovarian cycle. At puberty, GnRH secretion increases in both frequency and...
01:22Hormonal Regulation of the Menstrual Cycle
At puberty, GnRH begins a pulsatile release pattern, which triggers the anterior pituitary gland to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The frequency and amplitude of GnRH pulses vary across the menstrual cycle, with faster pulses favoring LH release and slower pulses favoring FSH...
01:27Ovarian Cycle
01:22Target Cell Response to Hormones
Notably, the cellular response can be regulated by altering the number of receptors expressed in the cell. For example, prolonged exposure to elevated hormone levels results in a gradual decline or down-regulation in the number of receptors for that specific hormone on the cell surface. Conversely, in response to low hormone levels, cells may use up-regulation, producing an...
01:24Gonadal and Placental Hormones
In males, testosterone is the primary gonadal androgen. It plays a central role in the maturation of male reproductive organs — the penis and testes. Additionally, testosterone is instrumental in the development of secondary sexual characteristics — a deep voice as well as facial and pubic hair...
01:20Folliculogenesis