Abstract
ObjectiveCombination of transcriptomic and retrospective clinical data, to assess anti-Mullerian hormone (AMH) functionality at a cumulus cell level and evaluate AMH potential as a suitable marker for IVF outcomes (oocytes retrieved, number of day 3 embryos, gestation outcomes).DesignRaw RNA-sequencing data of cumulus cells sourced from younger (n = 10) patient group (group A) (age 29 (1 year of age), baseline FSH 7.4 (0.5 mIU/ml), AMH 4.67 (1.56 ng/ml)) and older (n = 10) patient group (group B) (age 43 (± 0.55 years of age), baseline FSH 8 (0.8 mIU/ml), AMH 1.07 (0.44 ng/ml)) were employed to derive transcriptomic differences among high vs. low AMH groups. We collected retrospectively patient data from 80 infertile patients selected according to pre-specified inclusion criteria.SettingPublicly available raw RNA-sequencing data were retrieved from the SRA database of NCBI resource GEO Accession (GSM21575/35-44; GEO Accession: GSM21575/45-55). Retrospective data were collected from referrals to the Institute of Reproductive Medicine, Lito Hospital of Athens and the Institute of Life, Iaso Hospital of Athens, between the periods of March 2015 and April 2018.Intervention(s)A fixed human menopausal gonadotropin (hMG) antagonist protocol was used for all patients. All patients had serum AMH levels measured within a 3-month period prior to stimulation and serum levels of FSH and estradiol (day 2 of menstrual cycle; E2) (Clinical Trial code NV24042014).Main outcome measure(s)The primary outcomes were identification of transcriptomic variations among high (group A) vs. low (group B) AMH patients. Retrospective data primary outcomes were number of oocytes retrieved, fertilized successfully (grades A and B, day 2 embryos), and total number of day 3 embryos. Secondary outcome was live birth rate. Finally, we compared primary outcomes with AMH and FSH level as well as their genetic pathways (interacting genes) to demonstrate the predictive accuracy.ResultsEssential players of the AMH signaling cascade, namely, SMAD1, SMAD4, SMAD5, ALK1, and LEF1, were significantly upregulated in group A (n 10) transcriptome. This biological clue was further supported by retrospective clinical data (n 80 participants), where AMH was positively correlated with both oocytes retrieved and fertilized as well as number of day 3 (grades A and B) embryos from patients undergoing IVF, in a statistically significant manner. AMH was further positive trend of association with successful pregnancy outcomes.ConclusionOverall, this study offers new insight on AMH effects upon cumulus cells and new aspects on how AMH might promote oocyte integrity and embryo viability at a biochemical level as well as add to the current body of evidence supporting AMH clinical potential as a more sensitive marker of IVF outcomes in comparison with FSH, regarding numbers of oocytes received and high-quality day 2 and day 3 embryos.
Highlights
Infertility presents a complex disorder with a vast range of implications spanning from medical and psychological to socioeconomic consequences, affecting 20–80 million people across the world
These variations may have been due to parameters that may have been recorded such as anti-Mullerian hormone (AMH), FSH, and E2 levels [Fig. 2a–c] or not affecting cumulus gene expression [34,35,36]
We further explored the functionality of genes that displayed strong differential expression with a bioinformatic approach (Fig. 3)
Summary
Infertility presents a complex disorder with a vast range of implications spanning from medical and psychological to socioeconomic consequences, affecting 20–80 million people across the world. The new classification criteria of infertile women, according to their ovarian response to OS—the POSEIDON criteria—provide more precise guide in the management of these women than ESHRE (Bologna) criteria [2] Both existing criteria (Bologna and POSEIDON) use antral follicle count (AFC) and anti-Mullerian hormone (AMH) levels as the ovarian reserve tests, many clinicians still commonly employ FSH as marker of ovarian reserve in initial patient assessment prior to IVF cycle initiation [3]. AMH acts upon both granulosa cells and the oocyte to promote dominant follicle selection while FSH promotes follicle development and estradiol production [4, 5] (Fig. 1) Both hormones play central roles in the orchestration of gonadal function and reproduction. The identification of a non-invasive reliable predictor of OS success remains a significant goal in reproductive medicine
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