Australasian Science: Australia's authority on science since 1938

Egg Supply and Demand

Credit: Maridav/Adobe

Credit: Maridav/Adobe

By Karla Hutt & Jock Findlay

Understanding the relationship between the number of healthy eggs stored in the ovaries and the length of the fertile lifespan will lead to more accurate predictions about how long each woman will remain fertile.

Globally, more women over the age of 30 are giving birth than in any previous generation. In fact, one in seven Australian women have their first child at 35 years of age or older. Considering our grandmothers usually had their first birth in their early twenties, this is a dramatic change.

The striking increase in maternal age during the preceding four decades can be attributed to a range of medical, social and societal changes, including widespread access to the oral contraceptive pill and improved career opportunities for women. Pregnancy may also be delayed due to circumstances beyond a woman’s control, including illness or lack of a suitable partner.

Regardless of the reasons for postponing pregnancy, the increasing age of first time motherhood presents significant problems because fertility declines steeply after the age of 35 years. However, it does not do so at the same rate for every woman, and the age when fertility may become compromised varies considerably within the population. This conundrum leads many women to ask probing questions about their own fertility. These questions vary in their specifics, but in a general sense can be boiled down to the desire to know how much time a woman has left to start a family.

To help address this question, our research is focusing on the factors that determine how many eggs are stored in the ovaries and the relationship between that number and the length of the fertile window. We have even taken this basic question a step further by using specially modified mouse models to investigate the possibility that fertility can be prolonged by increasing the number of available eggs.

At present a crystal ball allowing us to peer into our future fertility does not exist. Most people are familiar with the concept that fertility declines with age. Even so, many are lulled into a false sense of security by frequent reports of celebrities in their forties conceiving and bearing children with apparent ease. Some women are taken by surprise upon discovering that conceiving and having a healthy child may be challenging or perhaps impossible for them in their late thirties. Many believe that fertility treatments will enable them to have a child, no matter what their age.

However, it is not always so straightforward. If no eggs are left in the ovary, then no amount of IVF will produce a baby. Even if eggs remain in the ovary, their quality may be insufficient to support a healthy pregnancy. In these cases, a shortfall in the egg supply chain means the demand for motherhood cannot be easily accommodated. Clearly, the decision to delay childbearing is not without its risks.

Being able to precisely predict future fertility would obviously be of enormous benefit to women, enabling them to better plan their futures and make informed reproductive choices. However, predicting future fertility is challenging. This is because reproductive lifespan is intimately linked to the quantity and quality of eggs stored in a female’s ovaries, and egg quantity and quality are influenced by a plethora of genetic and environmental factors.

A baby girl is born with a finite number of eggs stored in her ovaries, which we call the ovarian reserve, and it is not possible to make new eggs after birth. The implications of this biological limitation are twofold:

  • the ovaries must be endowed with enough healthy eggs at birth to sustain fertility for a sufficient period of time to allow for reproduction; and
  • an egg ovulated by a women in her forties was actually made before she was even born and has been sitting dormant in her ovaries ever since.

Over time, for reasons we only partially understand, the eggs lose quality, which we define as their capacity to generate a healthy baby following fertilisation. Additionally, the quantity of available eggs gradually decreases with each passing year, through natural cell death or ovulation.

Consequently, when the supply is used up, or only low-quality eggs remain, pregnancy may no longer be possible. Under these circumstances, the only option for pregnancy is to “borrow” an egg from a younger woman.

We know that the number of eggs established in the ovaries at birth combined with the rate at which that number declines throughout life impacts greatly on the duration of fertility. However, both of these factors vary considerably between individuals because the initial number of eggs found in the ovary at birth and the subsequent rate of depletion are influenced by many things.

One of the known variables involves the massive loss of eggs that occurs as part of normal ovarian development. It surprises many women to learn that, for largely unknown reasons, approximately two-thirds of the eggs made in the developing foetal ovary are destroyed before birth, never having the chance to develop further and ovulate. Differences in the rate of egg loss during this time likely contributes to the vastly different number of eggs found in individuals at birth, and is likely to be pre­determined to some degree by genetics.

Furthermore, the rate of loss before and after birth can be influenced by a plethora of external factors. Exposure to cigarette smoke and other environmental toxicants, as well as anti-cancer treatments, all hasten depletion of the ovarian reserve. However, determining to what extent an individual’s egg supply may be depleted by these factors is not yet possible.

On the other hand, claims that women in their forties can conceive easily if they maintain a healthy lifestyle should be regarded with caution. While a healthy lifestyle is important for a healthy pregnancy, there is currently scant evidence that healthy eating and fitness will slow the natural loss of eggs, improve the quality of an old egg or prolong fertility beyond its natural duration.

The nuances of the relationship between egg number and length of the fertile lifespan are unclear. At this point there is no formula that can be applied to enable us to say to a woman: “You have x number of eggs, which means you have y time left to start a family”. Moreover, we cannot accurately measure the number of eggs that a woman has without removing her ovaries. Available ovarian reserve tests, such as serum levels of anti-Mullerian hormone, may provide reassurance about a woman’s current ovarian reserve and fertility status, but such tests cannot tell a woman how long it will remain so.

Because of these current deficiencies in our understanding, there is a great need to identify the genes and proteins responsible for controlling egg loss, both during ovarian development in the foetus and postnatal life. Our laboratories have found that preventing the natural loss of eggs early in life, by manipulating key death pathways in the egg, can extend the fertile lifespan – at least in mice.

We have found that two cell death-promoting proteins called PUMA and BMF play an important role in determining how many eggs are initially established and then maintained in the ovary. In mice, elimination of PUMA prevents the natural loss of eggs in the developing embryo, and consequently females are born with twice as many eggs as normal. Interestingly, these excess eggs are eliminated prior to adulthood by an unknown mechanism, with loss of fertility occurring at the normal age.

In contrast, BMF-deficient mice are born with normal egg numbers, but the rate of egg loss after birth is reduced. This means that more eggs are maintained in the ovary throughout reproductive life, and fertility is prolonged by approximately 2 months. While this may not seem like much, it equates to a 25% longer fertile lifespan in the mouse. In women, this would mean extending the fertile lifespan by as many as 6 years.

While extending the length of the fertile lifespan in women using this strategy is not feasible, our work demonstrates that reducing egg loss early in life leads to increased egg availability in adulthood, which confers longer fertility.

Furthermore, it has been known for many years that situations in which egg number is severely depleted, such as through exposure to anti-cancer treatments, often lead to early loss of fertility and menopause, but it was not clear if the converse – increasing egg number – would lead to longer fertility. Studies such as ours provide support for the idea that egg number does play a significant role in controlling the fertile lifespan.

While conceptually this is a significant finding, the problem we face is that we still have no means of determining with any accuracy how many eggs a female has and precisely how long that supply will last.

The long-term goal of our research, as well as many others in the field, is to fully understand the relationship between egg number and fertility to enable the development of accurate ovarian reserve tests that could be used to advise women about their future fertility.

In the meantime, delayed child birth remains a risky business.

Karla Hutt is a Senior Research Fellow at the Department of Anatomy and Developmental Biology, Monash University. Jock Findlay is a Distinguished Scientist at the Hudson Institute of Medical Research.