Why Nature Makes Millions of Oocytes—Then Discards 99%

In humans and mice, oocytes—the precursor cells that can ultimately become eggs—are formed during fetal development, yet most of them disappear before reaching full maturity.
In humans, the germ cell pool decreases drastically from an estimated 5–7 million in the fetus to 1–2 million at birth, and then to about 300,000–500,000 by puberty. Over the entire reproductive lifespan, only ~400–500 oocytes are actually ovulated.
Why would nature invest so much energy to produce millions of cells, only to eliminate more than 99% of them?

At present, three major mechanisms (or “hypotheses”) are often discussed:

• Death by self-sacrifice: during germline cyst breakdown, nurse cells transfer resources to a “main” oocyte and then die.
• Death by neglect: during follicle formation, oocytes become dependent on survival signals from surrounding granulosa cells; those receiving insufficient signals undergo cell death.
• Death by defect: during meiosis, cells with errors (e.g., failed recombination or unrepaired DNA damage) are removed as a quality-control process.

1. Death by self-sacrifice: cyst breakdown and nurse cells

The first major wave of germ-cell apoptosis occurs around the time of cyst breakdown (mid-gestation in humans; around birth in mice).

• Mechanism: early germ cells form a “germline cyst,” a cluster-like structure in which cells are connected via intercellular bridges, allowing cytoplasmic continuity. Within this structure, a primary oocyte and accompanying nurse cells are specified, and nutrients/resources are transferred from nurse cells to the primary oocyte. When the cyst breaks apart and primordial follicles form, many nurse cells undergo apoptosis and are eliminated.
• Interpretation: if this wave of apoptosis were artificially blocked, it might allow survival of oocytes that failed to receive sufficient resources—potentially lowering average oocyte quality.

2. Death by neglect: survival signaling from granulosa cells

After primordial follicles form, oocyte survival becomes highly dependent on signals from surrounding somatic cells.

• The Kit–KitL axis: binding of the Kit receptor on oocytes to Kit ligand (KitL; also known as SCF, stem cell factor) produced by granulosa cells acts as a key survival “lifeline.” This signaling activates the PI3K–Akt pathway and helps maintain the balance of Bcl-2 family proteins toward survival.
• Evidence and an open question: prior work (e.g., Morita et al., 1999) reported that adding SCF + LIF (leukemia inhibitory factor) to ovarian organ culture dramatically improves survival. However, despite granulosa cells presumably being present in organ culture, that study did not fully explain why additional SCF + LIF further increases follicle survival. One possibility is that loss of in vivo blood supply (and thus systemic factors) changes the signaling environment in culture. Interestingly, supplementation with IGF-1—thought to be produced by the fetal liver—has also been reported to increase follicle survival.

3. Death by defect: eliminating abnormal cells

Because oocytes must undergo meiosis to transmit the genome to the next generation, they necessarily perform meiotic recombination. This is a highly precise process; passing on mistakes would increase the risk of chromosomal abnormalities in offspring. Therefore, there is strong selective pressure to actively eliminate “damaged” cells.

• Meiotic checkpoint: during prophase I, DNA recombination occurs. If DNA double-strand breaks (DSBs) are not properly repaired, the oocyte becomes a potential source of heritable chromosomal errors and is eliminated.
• TAp63: a key player is TAp63, a p53 family member. It is sometimes described as the “guardian of the female germline,” because upon sensing DNA damage it can rapidly trigger apoptosis.

Conclusion: “quality over quantity”

Oocyte apoptosis is not merely a loss; it is a normal biological function that contributes to the production of healthy eggs.

1. Resource allocation: concentrate limited resources into the most suitable cells (cyst breakdown).
2. Genetic integrity: remove cells with damaged DNA (TAp63-dependent checkpoint).

For research and intervention, the goal may be to prevent unnecessary loss due to insufficient signaling (“death by neglect”) while preserving quality-control death (“death by defect”)—in other words, to find the right balance between protection and selection.

References

Tilly JL. “Commuting the death sentence: how oocytes strive to survive” (Nat Rev Mol Cell Biol, 2001)