A central dogma of reproductive biology is that in mammalian females there is no capacity for oocyte production postnatally. Because oocytes enter the diplotene resting stage of meiosis in the fetus and persist in this stage until ovulation, much of the DNA, proteins, and messenger RNA (mRNA) necessary for development of the preimplantation embryo is synthesized by this stage. At the diplotene stage, a single layer of 8 to 10 granulosa cells surround the oogonia to form the primordial follicle. The oogonia that fail to become properly surrounded by granulosa cells undergo atresia (68). The remainder proceeds with follicular development. Thus, most oocytes are lost during fetal development, and the remaining follicles are steadily “used up” throughout the intervening years until menopause.
Evidence has begun to challenge this theory. Studies in the mouse showed that production of oocytes and corresponding folliculogenesis can occur well into adult life (69). The reservoir of germline stem cells responsible for this oocyte development appears to reside in the bone marrow (70). It is not clear whether such stem cells exist in adult humans, and if they do, what clinical function they might provide.
Meiotic Arrest of Oocyte and Resumption
Meiosis (the germ cell process of reduction division) is divided into four phases: prophase, metaphase, anaphase, and telophase. The prophase of meiosis I is further divided into five stages: leptotene, zygotene, pachytene, diplotene, and diakinesis.
Oogonia differ from spermatogonia in that only one final daughter cell (oocyte) forms from each precursor cell, with the excess genetic material discarded in three polar bodies. When the developing oogonia begin to enter meiotic prophase I, they are known as primary oocytes (71). This process begins at roughly 8 weeks of gestation. Only those oogonia that enter meiosis will survive the wave of atresia that sweeps the fetal ovary before birth. The oocytes arrested in prophase (in the late diplotene or “dictyate” stage) will remain so until the time of ovulation, when the process of meiosis resumes. The mechanism for this mitotic stasis is believed to be an oocyte maturation inhibitor (OMI) produced by granulosa cells (72). This inhibitor gains access to the oocyte via gap junctions connecting the oocyte and its surrounding cumulus of granulosa. With the midcycle LH surge, the gap junctions are disrupted, granulosa cells are no longer connected to the oocyte, and meiosis I is allowed to resume.
Follicular Development Follicular development is a dynamic process that continues from menarche until menopause. The process is designed to allow the monthly recruitment of a cohort of follicles and, ultimately, to release a single, mature, dominant follicle during ovulation each month.
The initial recruitment and growth of the primordial follicles is gonadotropin independent and affects a cohort over several months (73). The stimuli responsible for the recruitment of a specific cohort of follicles in each cycle are unknown. At the primordial follicle stage, shortly after initial recruitment, FSH assumes control of follicular differentiation and growth and allows a cohort of follicles to continue differentiation. This process signals the shift from gonadotropin-independent to gonadotropin-dependent growth. The first changes seen are growth of the oocyte and expansion of the single layer of follicular granulosa cells into a multilayer of cuboidal cells. The decline in luteal phase estrogen, progesterone, and inhibin-A production by the now-fading corpus luteum from the previous cycle allows the increase in FSH that stimulates this follicular growth (74).