Increasing telomerase enhanced steroidogenic genes expression and steroid hormones production in rat and human granulosa cells and in mouse ovary

Telomerase, a ribonucleoprotein responsible for telomere re-elongation, is important for male and female fertility. Several factors, including the steroid hormone estrogen, regulate the expression of Telomerase Reverse Transcriptase (TERT), which one of its non-canonical functions is gene expression regulation. The steroidogenesis process is regulated principally by transcription of genes encoding steroidogenic enzymes, but it is not clear if TERT non-canonical functions affect the expression of steroidogenic genes. Here we investigated this new notion by increasing TERT expression and activity in granulosa cells (GCs) derived from rat and from women that underwent in vitro fertilization (IVF) procedures and in vivo in mouse ovary. We show that gonadotropin enhanced the expression of TERT in rat GCs. Overexpression of human- TERT enhanced the expression of steroidogenesis genes in gonadotropin-stimulated rat GCs. Moreover, treatment with TERT increasing compounds (AGS) alone enhanced the expression of the steroidogenic genes in both rat and human GCs and in vivo in mouse ovary, while telomerase inhibitor reduced their expression. Treatment with AGS compounds, together with gonadotropin stimulation, additively increased steroidogenic gene expression. Enhancing TERT expression and activity increased the level of progesterone in mouse blood and in the medium of rat GCs and estrogen in women derived pre-ovulatory luteinized GCs. These data suggest that increasing TERT in GCs by pharmaceutical compounds enhanced steroidogenesis and the production of steroid hormones that are essential processes in human and animal reproduction. These data also suggest a novel possible strategy for the enhancement of the production of steroid hormones.