The oocyte, or egg cell, is the female gamete. It carries the mother’s half of the chromosomes, but it also supplies almost everything an early embryo needs before the embryo’s own genes become active: stored messenger RNAs, proteins and organelles. Research on the oocyte therefore asks two related but distinct questions. Can a given egg be fertilised? And, if it is, can it support an embryo through development? The second property, called developmental competence, is what clinicians and biologists usually mean by “egg quality”.
A cell formed before birth
Oocytes are formed in the fetal ovary. They enter meiosis, the special cell division that halves the number of chromosomes, and then stop part-way through its first stage. In mice this pause lasts weeks to months; in women it can last from about ten to fifty years, because an oocyte is not released until the follicle that encloses it is recruited to ovulate. Throughout this time the oocyte lives inside a follicle, surrounded by supporting somatic cells.
For most of the twentieth century it was taught that the stock of oocytes is fixed at birth. In 1951 a review by Zuckerman concluded that oocyte formation ceases by the time of birth, a view that became textbook dogma. In 2004 a report of mitotically active, oocyte-forming germ cells in adult mouse ovaries reopened the question, and later studies described so-called oogonial stem cells in several species, including humans. Other laboratories could not reproduce key findings in mice and monkeys, and oocyte-like cells derived from human ovarian cultures have not been shown to reach the mature stage needed for fertilisation. The debate remains open; clinical thinking about ovarian ageing still rests on the idea of a finite pool.
Growth: a partnership with the follicle
While it grows, the oocyte enlarges and stockpiles maternal messenger RNA. By the time it is fully grown, transcription has largely shut down, so the later steps of maturation depend on translating RNAs that were stored earlier. The oocyte does not grow alone. The innermost follicle cells, the cumulus cells, send fine cytoplasmic extensions called transzonal projections through the zona pellucida, the glycoprotein coat around the egg, and connect to it by gap junctions. Through these channels the cumulus cells pass small molecules, including energy-rich compounds derived from glucose, which the cumulus cells process more readily than the oocyte itself.
The traffic runs in both directions. The oocyte secretes growth factors of the TGF-β family, notably GDF9 and BMP15, which steer the proliferation and differentiation of the surrounding cells, promote expansion of the cumulus before ovulation and hold back premature luteinisation. Some of the clearest evidence came from sheep genetics:
- Ewes carrying one copy of certain BMP15 variants, such as the Inverdale mutation, ovulate more eggs than usual, while ewes with two copies are sterile, with follicles that stall at an early stage.
- Mutations in GDF9 have similar effects, and the high-prolificacy Booroola trait was traced to a change in a BMP receptor gene.
- Because these factors are made only by the oocyte, the findings showed that the egg itself helps decide how many follicles ovulate. In women, BMP15 variants have been linked to premature ovarian failure.
Meiotic arrest and maturation
Classic experiments by Pincus and Enzmann in 1935, and by Edwards in 1965, showed that oocytes taken out of their follicles resume meiosis spontaneously. Something in the follicle was therefore holding them in arrest. The mechanism was clarified decades later. A high level of the signalling molecule cyclic AMP inside the oocyte keeps meiosis on hold. Granulosa cells produce cyclic GMP, under the control of C-type natriuretic peptide and its receptor NPR2, and this cyclic GMP passes into the oocyte through gap junctions, where it blocks the enzyme that would otherwise break down cyclic AMP.
The surge of luteinising hormone (LH) that precedes ovulation dismantles this system. Cyclic GMP production falls, EGF-like growth factors such as amphiregulin spread the signal through the follicle, cyclic AMP in the oocyte drops and the cell-cycle machinery restarts. The nucleus breaks down, chromosomes are separated in the first meiotic division, and the egg pauses again at metaphase of the second division, the mature stage at which it can be fertilised. In parallel, a programme of “cytoplasmic maturation” reorganises organelles and switches the translation of hundreds of stored RNAs on or off. The two programmes must be coordinated: an egg that has extruded its polar body and looks mature is not necessarily able to support an embryo.
What makes a good egg?
The best-documented cause of poor egg quality is chromosomal error. Embryos with an extra or missing chromosome account for at least 10% of human pregnancies, and the proportion may exceed 50% for women approaching the end of their reproductive lifespan. Most trisomies arise from errors in the mother’s eggs, and the risk climbs steeply in the decade before menopause. Several mechanisms are thought to contribute:
- gradual weakening of the protein links (cohesion) that hold paired chromosomes together during the long arrest;
- failure of crossing-over in the fetal ovary, which leaves some chromosome pairs poorly tethered from the start;
- a spindle assembly checkpoint that is less stringent in female than in male meiosis, so errors are not always caught.
How much each mechanism matters is still debated. Beyond chromosomes, much of the research collected in this archive explores how the follicular environment, including its glucose and fatty-acid content, influences competence, often in cattle and pigs as well as in mice. In human studies, a higher lipid content in cumulus cells has been associated with lower pregnancy rates. No single biomarker of egg quality is yet in routine use, although candidate molecules measured in follicular fluid are under study.
From the laboratory to the clinic
Knowledge of oocyte maturation underpins assisted reproduction. In vitro maturation of immature oocytes is possible, but stripping away the cumulus cells impairs fertilisation and embryo yield, and researchers regard culture conditions as still open to improvement. Egg freezing is another application. The UK regulator, the HFEA, reports that vitrification (ultra-rapid freezing) is more successful than older slow-cooling methods, that egg quality and quantity decline with age, and that freezing is no guarantee of a future baby. Since July 2022, UK law allows eggs to be stored for up to 55 years, with consent renewed every ten years. Related techniques are covered on the cryopreservation and fertility preservation page, and the follicle that nurtures the oocyte on the ovarian follicles and ovulation page.
Established and still debated
It is well established that oocytes arrest in meiosis for long periods, that the follicle maintains this arrest through a cyclic nucleotide signalling system released by LH, that oocyte-secreted factors shape follicle development, and that chromosomal errors in eggs rise with maternal age. Still debated are the existence and physiological importance of oogonial stem cells in adult ovaries, the relative weight of the different causes of age-related aneuploidy, and whether a reliable, non-invasive test of egg quality can be developed.
Sources
- Conti M, Franciosi F, Human Reproduction Update, 2018 — Acquisition of oocyte competence to develop as an embryo: integrated nuclear and cytoplasmic events (doi:10.1093/humupd/dmx040)
- Nagaoka SI, Hassold TJ, Hunt PA, Nature Reviews Genetics, 2012 — Human aneuploidy: mechanisms and new insights into an age-old problem
- Xie J, Xu X, Liu S, Frontiers in Cell and Developmental Biology, 2023 — Intercellular communication in the cumulus–oocyte complex during folliculogenesis: a review (doi:10.3389/fcell.2023.1087612)
- Fabre S et al., Reproductive Biology and Endocrinology, 2006 — Regulation of ovulation rate in mammals: contribution of sheep genetic models (doi:10.1186/1477-7827-4-20)
- Martin JJ, Woods DC, Tilly JL, Cells, 2019 — Implications and current limitations of oogenesis from female germline or oogonial stem cells in adult mammalian ovaries (doi:10.3390/cells8020093)
- Human Fertilisation and Embryology Authority (HFEA), “Egg freezing” patient information
References from the journal archive
These articles were published in Reproduction, the Journal of Reproduction and Fertility or Reviews of Reproduction and are still cited at their old addresses on this domain. Each link leads to the publisher’s version through its DOI.
- PROPOSAL FOR A CLASSIFICATION OF OOCYTES AND FOLLICLES IN THE MOUSE OVARY
- Selective oocyte degeneration and impaired fertility in rats treated with the aliphatic monoterpene, Citral
- Effect of forskolin on the spontaneous maturation and cyclic AMP content of rat oocyte—cumulus complexes
- Effect of forskolin on maintenance of meiotic arrest and stimulation of cumulus expansion, progesterone and cyclic AMP production by pig oocyte—cumulus complexes
- Qualitative and quantitative structural changes during pig oocyte maturation
- Changes in intercellular coupling between pig oocytes and cumulus cells during maturation in vivo and in vitro
- Pregnancy resulting from cattle oocytes matured and fertilized in vitro
- Changes in protein synthesis and phosphorylation patterns during bovine oocyte maturation in vitro
- Differences in follicular morphology, steroidogenesis and oocyte maturation in naturally cyclic and PMSG/hCG-treated prepubertal gilts
- Effects of α-amanitin on nuclear maturation of porcine oocytes in vitro
- In vitro growth and maturation of pig oocytes
- Development to blastocysts of domestic cat oocytes matured and fertilized in vitro after prolonged cold storage
- Effect of follicle size and of the Fec B Booroola gene on oocyte function in sheep
- Effect of dominant follicle persistence on follicular fluid oestradiol and inhibin and on oocyte maturation in heifers
- Reduction of the developmental competence of sheep oocytes by inhibition of LH pulses during the follicular phase with a GnRH antagonist
- Meiotic competence of in vitro grown goat oocytes
- Improvement of quality of oocytes collected in the autumn by enhanced removal of impaired follicles from previously heat-stressed cows
- Maturation of human oocytes in vitro and their developmental competence
- Oocyte control of ovarian follicular development and function in mammals
- Evidence of oocyte donor cow effect over oocyte production and embryo development in vitro
- Independent activation of MAP kinase and MPF during the initiation of meiotic maturation in pig oocytes
- Genetic influences on ovulation of primary oocytes in LT/Sv strain mice
- Mitochondria in human oogenesis and preimplantation embryogenesis: engines of metabolism, ionic regulation and developmental competence
- Phospholipase Cζ causes Ca2+ oscillations and parthenogenetic activation of human oocytes
- The oocyte and its role in regulating ovulation rate: a new paradigm in reproductive biology
- Brain-derived neurotrophic factor promotes bovine oocyte cytoplasmic competence for embryo development
- Contribution of high p34cdc2 kinase activity to premature chromosome condensation of injected somatic cell nuclei in rat oocytes
- Cytoskeleton and cell cycle control during meiotic maturation of the mouse oocyte: integrating time and space
- Distinct roles for the mammalian A-type cyclins during oogenesis
- Non-esterified fatty acids in follicular fluid of dairy cows and their effect on developmental capacity of bovine oocytes in vitro
- Stops and starts in mammalian oocytes: recent advances in understanding the regulation of meiotic arrest and oocyte maturation
- An active protein kinase A (PKA) is involved in meiotic arrest of rat growing oocytes
- Interactive effects of granulosa cell apoptosis, follicle size, cumulus–oocyte complex morphology, and cumulus expansion on the developmental competence of goat oocytes: a study using the well-in-drop culture system
- Naturally suppressed apoptosis prevents follicular atresia and oocyte reserve decline in the adult ovary of Lagostomus maximus (Rodentia, Caviomorpha)
- Selective degradation of maternal and embryonic transcripts in in vitro produced bovine oocytes and embryos using sequence specific double-stranded RNA
- Alterations in epigenetic modifications during oocyte growth in mice
- Analysis of TATA-binding protein 2 (TBP2) and TBP expression suggests different roles for the two proteins in regulation of gene expression during oogenesis and early mouse development
- Association between human oocyte developmental competence and expression levels of some cumulus genes
- Carbohydrate metabolism by murine ovarian follicles and oocytes grown in vitro
- Dielectrophoretic behavior of in vitro -derived bovine metaphase II oocytes and zygotes and its relation to in vitro embryonic developmental competence and mRNA expression pattern
- Evaluation in mammalian oocytes of gene transcripts linked to epigenetic reprogramming
- In vitro development of mouse fetal germ cells into mature oocytes
- Biological interpretations of transcriptomic profiles in mammalian oocytes and embryos
- Comparative analysis of oocyte transcript profiles reveals a high degree of conservation among species
- Sequential exposure of porcine cumulus cells to FSH and/or LH is critical for appropriate expression of steroidogenic and ovulation-related genes that impact oocyte maturation in vivo and in vitro
- What can we learn from gene expression profiling of mouse oocytes?
- p63 null mutation protects mouse oocytes from radio-induced apoptosis
- Awakening the oocyte: controlling primordial follicle development
- Glycogen synthase kinase 3B in bovine oocytes and granulosa cells: possible involvement in meiosis during in vitro maturation
- Homozygosity for a single base-pair mutation in the oocyte-specific GDF9 gene results in sterility in Thoka sheep
- Oocyte quality in lactating dairy cows fed on high levels of n-3 and n-6 fatty acids
- Pyruvate prevents aging of mouse oocytes
- Regulation of intracellular pH during oocyte growth and maturation in mammals
- Temporal regulation of BMP2 , BMP6 , BMP15 , GDF9 , BMPR1A , BMPR1B , BMPR2 and TGFBR1 mRNA expression in the oocyte, granulosa and theca cells of developing preovulatory follicles in the pig
- The DAZL and PABP families: RNA-binding proteins with interrelated roles in translational control in oocytes
- cAMP pulsing of denuded mouse oocytes increases meiotic resumption via activation of AMP-activated protein kinase
- Cumulus cell gene expression following the LH surge in bovine preovulatory follicles: potential early markers of oocyte competence
- Effects of puberty and gonadotropins on the molecular events controlling meiotic resumption of mouse oocytes
- Endogenous folates and single-carbon metabolism in the ovarian follicle, oocyte and pre-implantation embryo
- Fibroblast growth factor 10 enhances bovine oocyte maturation and developmental competence in vitro
- On the origin of the maternal age effect in trisomy 21 Down syndrome: the Oocyte Mosaicism Selection model
- The pivotal role of glucose metabolism in determining oocyte developmental competence
- Altered expression of Armet and Mrlp51 in the oocyte, preimplantation embryo, and brain of mice following oocyte in vitro maturation but postnatal brain development and cognitive function are normal
- Endocytosis in the mouse oocyte and its contribution to cAMP signaling during meiotic arrest
- Oocytes in sheep homozygous for a mutation in bone morphogenetic protein receptor 1B express lower mRNA levels of bone morphogenetic protein 15 but not growth differentiation factor 9
- Potential upstream regulators and downstream targets of AMP-activated kinase signaling during oocyte maturation in a marine worm
- The integrin-binding motif RGDS induces protein tyrosine phosphorylation without activation in Bufo arenarum (Amphibia) oocytes
- Absence of seasonal changes in FSHR gene expression in the cat cumulus–oocyte complex in vivo and in vitro
- Ceramide and mitochondrial function in aging oocytes: joggling a new hypothesis and old players
- DNA methylation and mRNA expression profiles in bovine oocytes derived from prepubertal and adult donors
- Effects of species differences on oocyte regulation of granulosa cell function
- FSH withdrawal improves developmental competence of oocytes in the bovine model
- Bone morphogenetic protein 15 and fibroblast growth factor 10 enhance cumulus expansion, glucose uptake, and expression of genes in the ovulatory cascade during in vitro maturation of bovine cumulus–oocyte complexes
- Oocyte developmental failure in response to elevated nonesterified fatty acid concentrations: mechanistic insights
- Lipids and oocyte developmental competence: the role of fatty acids and β-oxidation
- Maternal age effect on mouse oocytes: new biological insight from proteomic analysis
- Changing expression and subcellular distribution of karyopherins during murine oogenesis
- Oocyte ageing and epigenetics
- Requirement of the transcription factor USF1 in bovine oocyte and early embryonic development
- Failure to launch: aberrant cumulus gene expression during oocyte in vitro maturation
- Genes of cellular components of morphogenesis in porcine oocytes before and after IVM