An Egg Economy

The Slow Triumph of the Oocyte

If you ever collected frog spawn from a pond in your schooldays or for your children, you may remember how quickly those embryos developed. Within 24 hours, they formed a blastula of about 4,000 cells. Human embryos progress far more slowly, yet even they seem brisk compared to the languid pace of oocytes (egg cells), which take weeks to reach full size. The slowness is deceptive. During that long, hidden period in the ovarian follicle, the oocyte is anything but idle. It is synthesizing RNAs and proteins, assembling organelles, and epigenetically programming its genome for the moment after fertilization, before the paternal genes begin to function.

Oogenesis—the making of eggs—lays the foundations for embryogenesis. No culture system, however refined, can compensate for starting life with a poor-quality egg.

The oocyte is a paradox: at once a generalist, the ancestor of every cell in the body, and a specialist at the same time, the sole partner of the sperm. It contributes more to early development than its microscopic counterpart, yet it is incomparably rarer. Over a lifetime, a woman will produce fewer than 400 mature eggs, while a man makes roughly two trillion sperm. Rarity breeds value—and, by a whimsical calculation, if donor human oocytes were priced like commodities, they would rank among the most precious objects on Earth, worth an estimated $250 million per gram!

Why Oocyte Research Matters

For these reasons and more, the oocyte is at the center of modern fertility research. It is the keystone for improving IVF success rates and for making treatment safer, more accessible, and more affordable. Superovulation has modestly increased egg yields—perhaps tenfold per cycle—but cannot be repeated indefinitely. True abundance may depend on two breakthroughs: growing oocytes from primordial follicles or creating eggs de novo from somatic cells, new goals known as in vitro gametogenesis (IVG) (see next post).

In the meantime, there is a transitional technology: in vitro maturation (IVM). After four decades of alternating optimism and disillusionment, IVM is again gaining traction. It offers a gentle prelude to IVF or (more often) ICSI, requiring little or no hormonal stimulation—a major cost and burden of conventional treatment.

Bring on the Immature Follicles

The IVM story began ninety years ago when Gregory Pincus—better known as the father of the Pill—and a Harvard colleague cultured oocytes from unstimulated rabbit ovaries. To their surprise, the cells matured spontaneously without the normal pre-ovulatory surge of luteinizing hormone.

Thirty years later in Cambridge, Robert Edwards—who would go on to pioneer IVF—aspirated oocytes from human ovarian biopsies. Many matured after 24–36 hours in culture and could be fertilized with donor sperm. Yet Edwards doubted that embryos derived from IVM would be fertile for clinical use, so he turned to natural-cycle or hormonally stimulated oocytes instead.

His caution was understandable, though perhaps overstated. Acceptable pregnancy rates have since been achieved in both animals and humans using IVM, though outcomes still trail conventional IVF. Even so, IVM offers unique advantages: reduced cost, lower risk for patients with polycystic ovarian syndrome (PCOS), and potential use in women with hormone-resistant ovaries or those seeking fertility preservation.

The first human birth following IVM occurred in 1983, reported by Lucinda Veeck in Virginia, who rescued an oocyte that failed to respond in a hormonal cycle and matured it successfully in culture. The field gained wider notice in 1991, when K.Y. Cha in South Korea reported several births from oocytes matured entirely in vitro without hormone stimulation. Around the same time, livestock researchers began applying IVM to accelerate genetic improvement by collecting eggs from prepubertal or even pregnant animals to shorten the generation time and achieved respectable pregnancy rates of about 25% per embryo transferred.

A version of IVM emerged in a colleague’s lab at McGill University, where a mild hormonal “priming” pulse of hCG or a GnRH agonist was given before egg retrieval. Although the logic behind this step was debated and added complexity for embryologists, clinics in Asia and elsewhere tried it.

I once reassured a pharmaceutical executive visiting me in Montreal that IVM wouldn’t undermine sales of recombinant FSH that his company had heavily invested in. Decades later, that reassurance still holds until future breakthroughs. Meantime, low-dose FSH priming is often used to increase the oocyte harvest by reducing follicular atresia. Success rates vary, but typically fall between 10 and 35%, depending on patient selection. Women with scant follicle reserves seen on ultrasound are unlikely candidates.

The Physiology of Pause

Pincus’s early finding revealed a key principle: the oocyte’s nuclear cycle—long arrested at an intermediate stage of meiosis—is actively suppressed within the follicle until the hormonal signal of ovulation lifts the brake. The oocyte is not autonomous. It depends on its surrounding granulosa cells, which are metabolically coupled and secrete local (paracrine) regulators.

Among the crucial molecular brakes are cyclic nucleotides. Phosphodiesterase inhibitors, which prevent cAMP breakdown, block maturation. More recently, C-type natriuretic peptide (cNP) has been identified as an upstream regulator acting through cGMP to sustain this meiotic arrest.

These insights have practical consequences. Oocytes retrieved prematurely for IVM can resume nuclear division before their cytoplasm is fully mature. Extending their culture time—via a biphasic system combining a pre-IVM “capacitation” phase with cNP as a suppressor and EGF-like peptides as boosters—has yielded encouraging results, notably from an Australian team developing CAPA-IVM (1) .

Research has moved beyond simply tweaking media formulas. It is now clear that slower, more physiological development yields better outcomes, and denuding the oocyte of its cloud of granulosa cells is detrimental. Attempts to co-culture with native granulosa cells faltered because those cells spontaneously change (luteinize) in vitro. The latest innovation is the engineering of granulosa-like cells from induced pluripotent stem cells (iPSCs) by overexpressing two key transcription factors. This patented approach, developed by a biotech firm in Texas, is currently in clinical trials (2).

High Stakes, Higher Standards

While IVM is not nearly as revolutionary as the prospect of IVG, it offers several advantages over conventional treatment. The safety of standard IVF procedures is well established after millions of births, yet every new variation must be scrutinized with the same care because the stakes could not be higher than ensuring the lifelong health of children conceived this way.

To date, no adverse outcomes have been linked specifically with IVM to my knowledge, either in humans or livestock. However, Large Offspring Syndrome in cloned or assisted-bred animals remains a cautionary tale, although less frequent now with serum substitutes in culture media. The equivalent condition of overgrown newborn babies is Beckwith–Wiedemann syndrome, which, along with Angelman syndrome, is an epigenetic disorder involving imprinted genes that has been associated with IVF, although fortunately very rare. Since DNA methylation is not completed until oocytes are nearly mature, it is reasonable to ask if premature maturation could affect the imprinting process. This is yet another reason why slower IVM is desirable.

Image: The Cosmic Egg, a universal symbol of creation (DALL-E 3)

References:

1. Gilchrist, Robert B.et al. “Oocyte in vitro maturation: physiological basis and application to clinical practice.” Fertility and Sterility, Volume 119, Issue 4, 524 – 539.
2. Piechota, Sabrina et al. “Human-induced pluripotent stem cell-derived ovarian support cell co-culture improves oocyte maturation in vitro after abbreviated gonadotropin stimulation.” Human reproduction (Oxford, England) vol. 38,12 (2023): 2456-2469.