Effects of Testosterone on Cumulus Cells Gene Expression in Patients with Diminished Ovarian Reserve

Diminished ovarian reserve represents a challenging condition in assisted reproductive technology. Androgens' actions are recognized as instrumental in folliculogenesis based on animal and human studies. Thus, we aimed at investigating whether testosterone pretreatment has an influence on gene expression of cumulus cells of diminished ovarian reserve patients. We included patients under 42 years-old presenting for IVF with diminished ovarian reserve (antral follicle count ≤ 6 and antimüllerian hormone < 1.2 ng/ml), between may/2018 and august/2019. Stratified randomization was performed and subjects were allocated into testosterone group (receiving transdermal testosterone gel pretreatment 1% 25 mg daily; N = 9) or control group (receiving standard ovarian stimulation; N = 9). Cumulus cells were collected following oocyte retrieval and RT-qPCR was conducted to evaluate gene expression differences in members of AKT signaling pathway, mTOR signaling pathway, IGF1, FSHR and AMH. Testosterone group patients showed a lower expression of AKT1 in cumulus cells as compared to control group subjects. Other evaluated target genes of the same pathway (FOXO1, FOXO3, PTEN), mTOR signaling pathway genes (mTOR, TSC1, TSC2), as well as IGF1, FHSR and AMH displayed no significant differences between groups. Testosterone pretreatment in diminished ovarian reserve patients down-regulates AKT1 gene expression in cumulus cells. The described profile could be linked to better oocyte reproductive potential, as cumulus cells related to competent oocytes might decide their fate (apoptosis) after completing their role in sustaining oocyte development during cyclic follicular recruitment. Transdermal testosterone pretreatment in diminished ovarian reserve patients down-regulates AKT1 in cumulus cells, possibly enhancing oocyte reproductive potential.