Ovarian ageing: what’s driving egg decline?

Medically reviewed by Mr. Ozkan Ozturk, consultant gynaecologist and specialist in reproductive medicine, CRGH.

When we talk about ovarian ageing, the conversation often focuses on one thing: running out of eggs.

But emerging research presented at the European Society of Human Reproduction and Embryology (ESHRE) suggests the picture is much more complex.

As we age, both the number and quality of eggs decline. Understanding why this happens is giving researchers new clues about what drives ovarian ageing and how fertility treatment could evolve in the future.

What happens to our ovarian reserve as we age?

Ovarian reserve refers to the number of eggs remaining in the ovaries. Clinically, we can estimate this using tests such as Anti-Müllerian Hormone (AMH) levels and an antral follicle count on ultrasound.

Through the earlier reproductive years, this decline tends to be quite gradual. From the mid-to-late thirties, however, the reduction becomes more significant and egg quality becomes increasingly important too.

With age, eggs are more likely to contain chromosome abnormalities, which can make fertilisation, healthy embryo development and pregnancy more difficult.

Eventually, as the number of remaining follicles falls, it can become harder to conceive.

What’s driving the ageing of our eggs?

One area receiving growing attention among scientists is hypoxia – a reduced supply of oxygen to tissues.

A developing follicle naturally exists in a relatively low-oxygen environment. In a younger ovary, the cells surrounding the egg appear to be well equipped to adapt.

They can respond in several ways:

• Encouraging the formation of new blood vessels through signalling pathways such as VEGF
• Adjusting their metabolism to cope with lower oxygen levels
• Activating mechanisms that help cells survive periods of oxygen stress

Research suggests that, as the ovary ages, these protective responses may become less effective. The cells surrounding the egg may no longer adapt to low oxygen as successfully, while the blood supply to ovarian follicles can also change.

At the same time, healthy ovarian tissue may gradually become affected by fibrosis, where excess connective tissue develops. This means ovarian ageing involves several connected changes, including:

• Reduced blood flow and vascularisation
• Lower oxygen availability
• Oxidative stress
• Inflammation
• Fibrosis within ovarian tissue

Research in both animal and human cells has linked severe follicular hypoxia with problems in chromosome separation – one of the biological processes that can contribute to chromosomally abnormal eggs and embryos.

So rather than age affecting the egg in isolation, scientists are becoming more interested in the environment around the egg as it develops.

Could this change fertility treatment in the future?

Potentially, although much of this research is still at an early or experimental stage.

Rather than thinking only about how many follicles can be developed during fertility treatment, researchers are now looking more extensively into the environment in which an egg develops.

Several areas are being explored:

• More personalised ovarian stimulation: One proposal is to avoid unnecessarily prolonged stimulation in women over 40 while waiting for follicles to become larger, with greater focus on the natural processes involved in follicle and egg development.
• Reducing ovarian fibrosis: Finerenone, a medicine currently used for kidney disease and heart failure, is being studied because it can reduce stromal fibrosis. Early research has shown promising results, including restored antral follicle development in aged mice. However, it’s not currently an established treatment for ovarian ageing or diminished ovarian reserve.
• Slowing follicle activation: Rapamycin acts on the mTOR pathway and is being studied for its potential to slow the recruitment of primordial follicles into the growing follicle pool. It may also promote autophagy, the process by which damaged cellular material is cleared.
• Targeting inflammation and oxidative stress: Researchers are also studying sirtuins, a family of proteins involved in reactive oxygen species, DNA repair and cellular metabolism. Compounds linked with sirtuin activity, including NAD-related molecules and resveratrol, are also under investigation.

What does this mean for me?

For patients, the main takeaway is that ovarian ageing appears to be about more than simply the number of eggs remaining.

Researchers are beginning to understand more about how blood supply, oxygen levels, oxidative stress, inflammation and fibrosis could affect the environment in which eggs develop. That doesn’t mean ovarian ageing can currently be reversed. But it might help explain why egg quality changes over time and why future fertility treatment could focus on follicle health, as well as egg numbers.

A balanced diet, regular exercise, avoiding smoking and maintaining good overall health remain sensible ways to support general and reproductive health. However, no food, supplement or lifestyle intervention has been shown to stop ovarian ageing.

A new way of thinking about ovarian ageing

We’re beginning to understand ovarian ageing as more than simply a decline in egg numbers.

Changes in blood supply, oxygen regulation, metabolism, inflammation and fibrosis appear to form part of a wider biological process that can affect the environment in which eggs grow.

Understanding these mechanisms could ultimately move reproductive medicine from focusing solely on the number of eggs available towards protecting the health of the follicle and the quality of the egg within it.

Many of the potential therapies being investigated are still some distance from routine clinical practice. But the more we understand about why eggs age, the more opportunities there might eventually be to develop new approaches to protecting ovarian function in the future.

 If you’re concerned about your ovarian reserve or age-related fertility changes, book a consultation with our team to better understand your fertility and the options available to you.