Mechanisms of primordial follicle activation and new pregnancy opportunity for premature ovarian failure patients

Abstract

Primordial follicles are the starting point of follicular development and the basic functional unit of female reproduction. Primordial follicles are formed around birth, and most of the primordial follicles then enter a dormant state. Since primordial follicles are limited in number and can't be renewed, dormant primordial follicles cannot be reversed once they enter the growing state. Thus, the orderly occurrence of primordial follicles selective activation directly affects the rate of follicle consumption and thus determines the length of female reproductive lifespan. Studies have found that appropriately inhibiting the activation rate of primordial follicles can effectively slow down the rate of follicle consumption, maintain fertility and delay ovarian aging. Based on the known mechanisms of primordial follicle activation, primordial follicle in vitro activation (IVA) technique has been clinically developed. IVA can help patients with premature ovarian failure, middle-aged infertile women, or infertile women due to gynecological surgery treatment to solve infertility problems. The study of the mechanism of selective activation of primordial follicles can contribute to the development of more efficient and safe IVA techniques. In this paper, recent mechanisms of primordial follicle activation and its clinical application are reviewed.

Keywords: In vitro activation; follicle; ovary; premature ovarian failure; primordial follicle activation.

FIGURE 1

Ovarian structure and follicular development pattern diagram (A) Ovarian structural pattern diagram. Follicles at different developmental stages constitute the basic structural and functional unit of the ovary. Primordial follicles are mainly distributed in the cortex, and growing follicles are mainly distributed in the medulla. The blood vessels in the ovary provide nutrients to the ovarian tissue and follicles, and the blood vessels around each follicle are relatively independent. (B) Follicular development pattern. The development of primordial follicles into primary follicles is independent of gonadotropins, a process called primordial follicle activation, also known as initial recruitment. The process from primary follicle development to ovulation is a gonadotropin-dependent stage. The process of primary follicle development into preantral follicles is called cyclic recruitment and is the FSH response phase. Antral follicles ovulate under the stimulation of the LH surge. After ovulation, the granulosa cells luteinize to form the corpus luteum.

FIGURE 2

Characteristics of tissue structure changes in primordial follicle activation A follicle consists of a single oocyte in the middle and several somatic cells surrounding it. Primitive follicle activation mainly has two characteristics of structural changes. On the one hand, after primordial follicle activation, the pre-granulosa cells slowly changed from flat to wedge-shaped, and then to cubic-shaped. On the other hand, the oocyte diameter increased.

FIGURE 3

Schematic model depicting the mechanisms of primordial follicle activation. Primordial follicle activation is a result of the delicate interaction of pre-granulosa cells and oocytes and the follicular microenvironment. The mTOR and WNT pathways in pre-granulosa cells, the mTOR and PI3K pathway in oocytes, and the communication channel (KITL-KIT) between pre-granulosa cells and oocytes are all necessary for primordial follicle activation. The mTOR signaling pathway in pre-granulosa cells initiates and regulates primordial follicle activation in adult ovary. The mTOR signal in the pre-granulosa cells senses changes in surrounding nutrients, pressure, etc., so that the pre-granulosa cells secrete more KITL. After KITL binds to the receptor on the oocyte membrane, it activates the PI3K signaling pathway in the oocyte, and then promotes the primordial follicle activation.