Interplay Between mTOR and Hippo Signaling in the Ovary: Clinical Choice Guidance Between Different Gonadotropin Preparations for Better IVF

Abstract

One of the most widely used types of assisted reproduction technology is the in vitro fertilization (IVF), in which women undergo controlled ovarian stimulation through the administration of the appropriate hormones to produce as many mature follicles, as possible. The most common hormone combination is the co-administration of gonadotropin-releasing hormone (GnRH) analogues with recombinant or urinary-derived follicle-stimulating hormone (FSH). In the last few years, scientists have begun to explore the effect that different gonadotropin preparations have on granulosa cells' maturation and apoptosis, aiming to identify new predictive markers of oocyte quality and successful fertilization. Two major pathways that control the ovarian development, as well as the oocyte-granulosa cell communication and the follicular growth, are the PI3K/Akt/mTOR and the Hippo signaling. The purpose of this article is to briefly review the current knowledge about the effects that the different gonadotropins, used for ovulation induction, may exert in the biology of granulosa cells, focusing on the importance of these two pathways, which are crucial for follicular maturation. We believe that a better understanding of the influence that the various ovarian stimulation protocols have on these critical molecular cascades will be invaluable in choosing the best approach for a given patient, thereby avoiding cancelled cycles, reducing frustration and potential treatment-related complications, and increasing the pregnancy rate. Moreover, individualizing the treatment plan will help clinicians to better coordinate assisted reproductive technology (ART) programs, discuss the specific options with the couples undergoing IVF, and alleviate stress, thus making the IVF experience easier.

Keywords: HP-hMG; Hippo; PI3K/mTOR/Akt; granulosa cells; ovarian stimulation; r-hFSH; r-hLH.

Figure 1

The PI3K/mTOR/Hippo pathways as guidance for clinical decision-making. Top: The PI3K/Akt/mTOR and Hippo pathways exert opposite effects on follicular development during the gonadotropin-independent phase. Activation of the PI3K pathway is crucial for each growing stage of the follicle, especially at the primordial and primary stages (30, 94). The Hippo pathway acts in a coordinated manner with PI3K in order to accelerate primordial follicle activation and promote follicular development (48). Bottom: The two pathways maintain their concerted action on follicular development during the gonadotropin-dependent phase of follicular growth, and especially on the maturation of granulosa cells and oocytes in the preovulatory follicles, thereby assuring regulated follicular activation and high oocyte quality (79, 96). Various disease states, aging, and the uniqueness of each woman, by influencing this balance, may affect the response to different gonadotropin preparations, and consequently, the outcome of the IVF. The activation status of key components of the PI3K and Hippo pathways may serve as a prognostic or predictive biomarker that can help clinicians guide treatment planning. (RG, Regulatory Genes).