Introduction

Mammalian follicle development starts during fetal (for human) or neonatal (for rodents) stages when primordial follicles are formed. Throughout reproductive life, most of this large but finite pool of ovarian primordial follicles remains dormant and only a small fraction of them initiates growth (Figure 6.1, initial recruitment) by uncharacterized intraovarian mechanisms [1]. Human follicles begin development during the fourth month of fetal life, and each human ovary contains ≈400000 follicles at birth. Unknown intraovarian mechanisms activate a small number of dormant primordial follicles at a rate of ≈1000 per month to initiate growth, and follicle depletion occurs at menopause when <1000 follicles remain [2]. For follicles not activated, the default pathway is to remain dormant for years or decades. The onset of menopause is associated with the near depletion of ovarian follicles. Although the menarche time for modern girls has advanced due to improved health and other environmental factors, the menopause time for women has remained constant at ~51 years of age.

Once started to grow, the activated primordial follicles with a single layer of flattened granulosa cells surrounding the primordial oocytes develop into primary follicles, secondary follicles, and then antral follicles. During follicle growth, multiple layers of granulosa cells are formed and the oocytes are enlarged in size. Throughout the reproductive life, primordial follicles undergo initial recruitment to enter the growing pool of primary follicles (Figure 6.1, initial recruitment). In the human ovary, more than 120 days are required for the primary follicles to reach the secondary follicle stage, whereas approximately 70 days are needed to grow from the secondary to the early antral stage [3]. Once initiated to enter the growing pool, ovarian follicles progress to reach the antral stage and minimal follicle loss is found until the early antral stage. Although multiple early antral follicles are present during each reproductive cycle, exposure to increasing levels of pituitary follicle-stimulating hormone (FSH) leads to the selection of a single (for human) or limited number of (for rodents) large preovulatory follicles (Figure 6.1, cyclic recruitment) destined for ovulation for each cycle. Follicles exposed to insufficient circulating FSH undergo atresia mediated by the apoptosis of granulosa cells [4]. Once selected, follicles develop an antral cavity filled with follicle fluid. Inside the antrum, an oocyte is surrounded by cumulus cells which are connected through gap junctions to mural granulosa cells.