Abstract
Bidirectional cross talk between granulosa cells and oocytes is known to be important in all stages of mammalian follicular development. Insulin-like growth factor (IGF) signaling is a prominent candidate to be involved in the activation of primordial follicles, and may be be connected to androgen-signaling. In this study, we interrogated transcriptome dynamics in granulosa cells isolated from human primordial and primary follicles to reveal information of growth factors and androgens involved in the physiology of ovarian follicular activation. Toward this, a transcriptome comparison study on primordial follicles (n = 539 follicles) and primary follicles (n = 261 follicles) donated by three women having ovarian tissue cryopreserved before chemotherapy was performed. The granulosa cell contribution in whole follicle isolates was extracted in silico. Modeling of complex biological systems was performed using IPA® software. We found the granulosa cell compartment of the human primordial and primary follicles to be extensively enriched in genes encoding IGF-related factors, and the Androgen Receptor (AR) enriched in granulosa cells of primordial follicles. Our study hints the possibility that primordial follicles may indeed be androgen responsive, and that the action of androgens represents a connection to the expression of key players in the IGF-signaling pathway including IGF1R, IGF2, and IGFBP3, and that this interaction could be important for early follicular activation. In line with this, several androgen-responsive genes were noted to be expressed in both oocytes and granulosa cells from human primordial and primary follicle. We present a detailed description of AR and IGF gene activities in the human granulosa cell compartment of primordial and primary follicles, suggesting that these cells may be or prepare to be responsive toward androgens and IGFs.
Highlights
Female fertility is dependent on continuous activation of primordial follicles from the resting dormant follicle pool
In preantral follicles isolated from women suffering from polycystic ovary syndrome (PCOS), an enhanced expression of IGF1R mRNA and protein was noted compared to controls (Stubbs et al, 2013)
The SSCEGs lists in granulosa cells from primordial and primary follicles (Ernst et al, 2018) were used to extract genes differentially expressed genes (DEG) between the two cell populations
Summary
Female fertility is dependent on continuous (monthly) activation of primordial follicles from the resting dormant follicle pool. Lambs born to dihydrotestosterone (DHT) or testosterone treated ewes showed the same pattern of dysfunctional early follicular development as the women suffering from PCOS. These examples emphasize the involvement of androgens in the early follicular development. Rhesus monkeys treated with testosterone showed an increase in the fraction of activated primary follicles and a 5-fold increase in IGF1R mRNA in the oocytes of primordial follicles, as well as an elevation in the intraoocyte IGF1 signaling (Vendola et al, 1999a,b). In the IGFsignaling system IGF binding proteins (IGFBPs) have in recent years received increased attention, because of their potential active modulating role of IGF-bioavailability. This modulating role might be important in terms of shifting from the dormant to the activated follicular stage (Hu et al, 2017)
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