What Determines Female Fertility?

As men age, the genetic quality of their sperm falls and this might also affect fertility. But what about women? The general trend in many countries is that couples are starting families later, which appears to be driven by financial, educational and career pressures. So how does deferring motherhood affect a woman’s fertility? Georgia Mills spoke to Francesca Duncan who is the Executive Director of the Center for Reproductive Science at Northwestern University...

Francesca - As women age there is a dramatic decline in both the number of the eggs within her ovaries as well as a decline in their quality. What people may not realise is that reproductive ageing in females begins when they reach their mid 30s, and continues all the way until menopause around age 50. So really, female reproductive ageing is one of the first organ systems in the human body to show signs of overt ageing.

Georgia - Do we know why this is?

Francesca - My laboratory and others around the world study what happens to egg quality with age and we really look at it from multiple angles. So what’s happening to the DNA inside of the egg, and what happens to other structures within the egg, and then what happens to the environment of the ovary where the egg is developing.

Georgia - So how did these three things affect the quality of an egg?

Francesca - We know that as women age their is an increase in the chromosomal abnormalities in that egg. The egg has to undergo a process of cell division called meiosis, and this process is really necessary for the egg to have its chromosomes so that when it unites with sperm, it can have the correct chromosomal complement in the embryo. With age, there is an increase in the abnormalities in this segregation process and this leads to incorrect chromosome numbers.

Georgia - These are kind of too much DNA in a cell?

Francesca - Yes, exactly. Or the incorrect number so it can have too much or too little and that can be bad for the outcomes of the embryo. Again, with age, the ability of that egg to undergo this process correctly deteriorates.

Georgia - What about the other items in the cell?

Francesca - There are also lots of things in the cell. The egg is one of the largest cells in the body and there are lots of structures called organelles, and you can think of these as little factories within the cell. Mitochondria, one of the organelles that we think about, especially with regards to ageing in the egg. Mitochondria is really the energy producing organelles of the body and they’re important for supporting the energenic demands of the egg as it develops and later the early embryo. With ageing, researchers have shown that there’s a decrease in the functional capacity of these mitochondria, as well as increase in the mutations in mitochondrial DNA, and this can negatively impact reproductive outcomes.

Georgia - I guess for an egg to get to a baby it’s going to take a lot of energy so, if something’s gone wrong in the energy factory of the cell, that’s kind of a big deal?

Francesca - Absolutely. And then the final part that we’re really interested in is what’s happening to the environment in which that egg is developing. Because there’s this complex environment of protein networks, as well as different cell types, where the egg develops in that ovary.

Our work has shown that there is really striking changes in that micro environment, so it become fibrotic or stiffer with age. You can actually physically feel this if you touch an animal ovary or a human ovary as it ages that it becomes tougher. This is also corresponding with a highly inflammatory environment which can damage the egg indirectly. So we’re really interested to see how we can study the mechanisms that underlie these changes in the environment.

Georgia - So to sum up: we’ve got a problem in the coding in the DNA of the cell; the energy factories are messing up, and the environment the egg is living in is worse. So what can we do about this; can this be mitigated?

Francesca - Yes. I think, as you just highlighted, it’s complex and it’s multi-factorial and so I think there’s unlikely to be just be one “catch all” intervention that will cure egg quality with age. But there are a lot of efforts underway now to figure out if there are ways we can target one or more of these pathways.

One example is supplementation of the animal or the impending mother with antioxidants, or mitochondrial nutrients that will improve the mitochondrial function. This has shown tremendous promise in mouse models in terms of extending fertility and improving fertility outcomes, but the data is less clear in humans.

Georgia - Something I’ve heard mention quite a lot is this idea of egg freezing. Could you just quickly explain what that is and then tell me does it work?

Francesca - Egg freezing really refers to the idea of undergoing a process of assisted reproduction to stimulate the ovaries to produce eggs that are then retrieved and frozen. What you’re probably referring to is this concept in relationship to ageing is “social egg freezing,” where younger women who want to sort of freeze their biological age in time.  Or another way to think about this is for fertility insurance and will have this process of oocyte freezing done when they’re young with the hopes that later one when they’re ready to start a family and they’re older, they will have young eggs to use to start their family.

Georgia - But you mentioned earlier, one of the problems her is that the environment itself is harsher?

Francesca - Right. There’s actually fairly compelling data from assisted reproductive technology cycles that shows from a egg donor studies, so eggs are obtained from women who are young and then they’re transferred back into women of advanced reproductive age. You can, in fact, have very high fertility rates in these older women when they use eggs from younger individuals.

But what the real big problem is with this process is that embryos are then being transferred into an older woman and we know that pregnancies in women of advanced maternal age have their own complications for both the mother and the offspring. This can include gestational diabetes, low birth weight, preterm birth, and stillbirth. So, basically, there’s some problems of having an older mother carrying the pregnancy to term.