It's not as simple as your age = your egg's age! Understanding the role of ova in reproduction; their functions, energy requirements and oxidative stress
From a traditional perspective, age is considered the primary factor in decreasing fertility (1)
In general, ageing is characterised by the progressive loss of function of tissue and organs. While of course ageing is a natural process, in this article we will use the oxidative stress theory (OST) to explain that the rate of ageing can increase and, potentially, slow down as well. OST is the hypothesis that age-associated functional losses are due to the accumulation of reactive oxygen and nitrogen species (ROS & RNS) -induced damages (2).
Oxidative stress can happen all over the body and can contribute to, among others, cardiovascular, kidney and brain function loss, especially as we age. The aim of this article is to explain how egg cells (oocytes, ova) are particularly vulnerable to ageing due to their unique role in reproduction.
There are two sections of this paper. In the first we’ll take you back to a bit of high-school biology and attempt to give a deeper explanation of oogenesis and spermatogenesis (egg and sperm development). This is quite complex as we take a microscopic look at cell development, but we’ll try to focus on the important stuff!
In the second section we’ll delve into the main purposes of this article, which is to show that egg cells are particularly vulnerable to ageing because of their enormous energy requirements and the potential impact of the by-products thereof.
At present there are no fertility treatments available that can bypass the need for egg health. IUI and IVF can bypass physical obstructions to fertility such as lack of cervical mucus, sperm mobility or blocked uterine tubes, but there is currently no external treatment for the processes mentioned in this article. There is growing research, however, that there are natural interventions available for supporting mitochondrial health and function, and improving antioxidant availability within the egg cells.
We’ll conclude with the argument that by understanding the processes of meiosis, mitosis and oxidative stress, there are opportunities for targeted interventions that can improve fertility outcomes, irrespective of your path to pregnancy.
Back to Basics: How does reproduction happen?
Cell division and replication happens constantly within the human body. This is called mitosis and each of our cells replicated contains the same genetic information (four strands of chromosomes).
Meiosis, on the other hand, is the process in which cells divide and create new cells with half the number of chromosomes so that when they meet at fertilisation, there is a complete set of DNA to pass on to the next generation. Meiosis is the formation process of both egg and sperm cells (gametes). Meiosis is divided into two stages, meiosis I and meiosis II. These stages are further divided into more phases, each with their own complex functions and processes, beyond the scope of this particular article.
Spermatogenesis and oogenesis are different in that oogenesis begins the first stage of meiosis in utero. These primary oocytes are then held in arrested development until the onset of puberty and then continue with the following phases in a cyclical manner until menopause. In contrast, spermatogenesis begins at puberty only and continues throughout adult life (4).
Not all the oocytes are developed at once: they are selected in groups from their primordial state. In a continuous process ruled by follicle stimulating hormone (FSH). In the early days of each menstrual cycle, one egg cell will be chosen to continue developing and ovulate (driven by estrogen and luteinizing hormone (LH)). If, for whatever reason, that particular egg does not complete the process there will be backups waiting to ensure that ovulation will occur.
The hours leading up to ovulation are crucial for reproduction: when the egg cell is mature enough to pass through the final phase of meiosis I and into meiosis II with the release of the extra chromosomes (known as the polar body). The final phases of meiosis II will complete only if egg and sperm meet at fertilisation. After the release of the second polar body, mitosis begins in the zygote - first producing a 2-cell embryo and ultimately the blastocyst (200 cells) which will implant in the uterine lining.
The purpose of this section has been to understand the process of meiosis in oogenesis. In the next section we’ll look more closely at the energy required for meiosis; the enormous mitochondrial power of egg cells and the potential impact on chromosomes
The role of mitochondria & oxidative stress in healthy reproduction
We often hear about age-associated chromosomal abnormalities when confronted with challenges in fertility. What does this mean? How does it happen and is there anything we can do about it? As previously mentioned, a traditional approach sees ageing as the primary contributing factor. But in the last few years new research is emerging around the role of mitochondria in the chromosomal process; the oxidative stress theory and how this may be contributing to rapid ageing; and the power of antioxidants to slow the rate of ovarian age.
In this section we’ll be looking at two factors potentially contributing to chromosomal abnormalities and egg health. One: the amount of mitochondrial energy required for optimal reproduction is huge. Two: the oxidative by-products of mitochondrial processes can cause damage if they are out of balance with antioxidants
Almost all cells in the human body contain mitochondria, which represent the energy requirements of that cell. Mitochondria are “the engine” of a cell and are responsible for that cell’s activity. A heart cell contains roughly 5000 mitochondria, a liver cell about 1000. A sperm cell contains 75, which are used for swimming to the egg and is then disposed of. A mature egg cell contains up to 600 000!
So we can see that an egg cell has an enormous role to play in reproduction (6), it is responsible for:
the final stages of meiosis 1 prior to ovulation
meiosis 2, including that of the sperm cell
mitosis in the zygote until the blastocyst implants in the uterine lining
If an egg cell has not reached optimal maturation in the months and days leading up to ovulation, it may not have sufficient mitochondria (quantity and quality) to drive these essential processes of reproduction and chromosomal abnormalities may occur. In our practice, we use various indicators to monitor egg health and maturity including hormone testing, the fertility awareness method, and symptoms of hormonal imbalance. A fertility doctor may also look at the size of the egg cell for viability.
If we continue with the metaphor of the engine, we may understand the theory of oxidative stress with more clarity too. A more powerful engine will produce more exhaust fumes. In the same way, a cell with more mitochondria will produce more potentially pollutive by-products. In the human body we call these free radicals or reactive oxygen and nitrogen species (ROS and RNS).
While these are a necessary function of growth and development of the egg, the oxidative stress theory of ageing is based on an imbalance between free radical production and antioxidants (2). In an egg cell with insufficient antioxidants present, an oversupply of free radicals can disrupt the meiosis process resulting in chromosomal abnormalities and obstructions to successful pregnancy. Balancing the supply and demand of energy from the mitochondria (free radicals and antioxidants) is, at present, considered one of the most critical factors in successful fertilisation (7).
In an optimally healthy situation, the egg cell would have sufficient mitochondria and the antioxidants (e.g from diet, sufficient sleep etc) required to “quench” or cancel out these free radicals but the reality is that thanks to our modern lifestyle, stress, environmental and inherited health (2) (8), many of our bodies are not in an optimal situation.
Conclusion
Throughout the process of maturation, the egg cell must acquire sufficient mitochondria and antioxidants to undergo the energy intensive processes of reproduction. Chromosomal abnormalities can occur if there are insufficient resources available for meiosis and the initial stages of mitosis in the zygote.
In our practice we view fertility as an indicator of health. This means that we look for root cause issues as to why obstructions to fertility are showing up. Age is often cited as the number one factor in declining fertility but we argue that egg cells are more vulnerable to ageing if exposed to environmental factors at certain times in their development
There are many potential contributing factors for both insufficient mitochondria and the impact of oxidative stress. In our practice we will look at your bio-individual make up and offer recommendations on dietary and lifestyle changes, as well as targeted supplementing for your individual needs. Book a free discovery call today and let’s work together for healthier eggs.
Sasaki H, et al. 2019. Impact of Oxidative Stress on Age-Associated Decline in Oocyte Developmental Competence Frontiers in Endocrinology. Published online 2019 Nov 22. doi: 10.3389/fendo.2019.00811
Ligouri et al. 2018. Oxidative stress, aging, and diseases. Clinical Aging. 2018 April 26; 13 757-772
Cooper GM. The Cell: A Molecular Approach. 2nd edition. Sunderland (MA): Sinauer Associates; 2000. Meiosis and Fertilization. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9901/
Maayan, Inbar, "Meiosis in Humans". Embryo Project Encyclopedia (2011-03-24). ISSN: 1940-5030 http://embryo.asu.edu/handle/10776/2084.
Mogessie, B. Meiosis in Mammalian Oocytes. Available from https://eggsnchromosomes.com/what-is-meiosis/
Scott Chappel, "The Role of Mitochondria from Mature Oocyte to Viable Blastocyst", Obstetrics and Gynecology International, vol. 2013, Article ID 183024, 10 pages, 2013. https://doi.org/10.1155/2013/183024
Van Blerkom J. Mitochondrial function in the human oocyte and embryo and their role in developmental competence. Mitochondrion. 2011 Sep;11(5):797-813. doi: 10.1016/j.mito.2010.09.012. Epub 2010 Oct 7. PMID: 20933103.
Ling Gu 2015 https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi Control of oocyte development: linking maternal nutrition and reproductive outcomes
Further research
John J.C. 2010 Mitochondrial DNA transmission, replication and inheritance: a journey from the gamete through the embryo and into offspring and embryonic stem cells,” Human Reproduction Update, vol. 16, no. 5, pp. 488–509, 2010.
Deborah Wing 2013 The Role of Mitochondria from Mature Oocyte to Viable Blastocyst
G. A. Thouas, A. O. Trounson, and G. M. Jones, “Effect of female age on mouse oocyte developmental competence following mitochondrial injury,” Biology of Reproduction, vol. 73, no. 2, pp. 366–373, 2005.
Rita Fields of Austin IVF Laboratory Embryo Grading. https://www.arcfertility.com/understanding-embryo-grading/