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Unlocking potential new treatments for premature ovarian insufficiency

Funded by Wellbeing of Women, Dr Roseanne Rosario is seeking to understand the connection between a genetic mutation and premature ovarian insufficiency, which could hold the key to new treatments.

Wellbeing of Women researcher, Dr Roseanne Rosario, standing in a laboratory

Premature ovarian insufficiency (POI) is when the ovaries stop working in women under the age of 40. It means the ovaries no longer produce oestrogen or release eggs, triggering premature menopause. When this happens, women are no longer able to become pregnant.

POI happens in about one in 100 women. Causes are mostly unknown but thought to include autoimmune diseases, infections such as malaria and tuberculosis, and chromosome abnormalities.

We don’t always know why POI happens, but we do know that one particular gene, Fragile X, is linked to a number of cases. This is called Fragile X-associated premature ovarian insufficiency, or FXPOI. Dr Roseanne Rosario Wellbeing of Women researcher

Dr Roseanne Rosario, from the MRC Centre of Reproductive Health at the University of Edinburgh, has confirmed that a mutation of the Fragile X gene stops specific proteins in the body from working properly, causing cells to die.

This research, funded by Wellbeing of Women, increases our understanding of the Fragile X gene and may ultimately support the development of effective treatments for FXPOI.

Dr Roseanne Rosario carrying out research to improve women's health

What is the Fragile X gene?

The Fragile X gene, also called FMR1, has two main functions – it helps to look after brain development and a woman’s reproductive ability.

Sometimes, these genes can change and mutate. It is not clear why this happens.

A mutation in this gene can cause an overproduction of Fragile X mRNA molecules. Women with this type of mutation can pass this onto their children. In their sons, there is a risk they could develop Fragile X syndrome, causing them to have autism or an intellectual disability.

How Fragile X genetic mutations affect oestrogen levels

Scientists believe that an overproduction of mRNA molecules, generated by a mutation in the Fragile X gene, trap other proteins and stop them from functioning properly. This causes other important cells to die.

Dr Rosario and her team had previously found evidence that granulosa cells – a type of cell that supports a woman’s eggs as they mature – might be affected by this mutation. This link is not well understood, so Dr Rosario tested this further by growing human granulosa cells with the Fragile X genetic mutation.

Using cutting-edge techniques, researchers were able to confirm that the Fragile X genetic mutation inhibits three specific proteins in the bodies that are vital for granulosa cells to work properly, and causes these cells to die.

Dr Rosario says:

“Increasing our understanding of the Fragile X gene is essential. Mutations in this gene not only have serious implications for women, potentially thrusting them into premature menopause, but it also has implications for their children."

In women with FXPOI, we have been able to show what happens to molecules, proteins and ovarian cells when a Fragile X genetic mutation occurs. This knowledge may help us unlock future treatments that can target this specific mechanism. Dr Roseanne Rosario

Dr Rosario and her team were able to show that granulosa cells affected by the Fragile X mutation produce mRNA molecules that form into ‘tangles’. These molecules carry the necessary genetic information needed to make proteins, but the mutation stops the creation of properly functioning proteins.

These proteins carry out important roles in the ovary and are required for granulosa cells to work properly. Without functioning proteins, the cells die.

Researchers discovered that specific proteins critical to the healthy functioning of granulosa cells were at lower-than-normal levels in ovaries affected by FXPOI compared with healthy ovaries.

Next steps

By taking a closer look at the origins of FXPOI, Dr Rosario and her team have provided a clearer insight into the connection between Fragile X genetic mutations and POI. This will assist researchers in finding potential future treatments that will have the ability to transform the lives of women and their children.

Wellbeing of Women is funding a number of research projects to improve women’s experiences of menopause and POI, including:

Wellbeing of Women is also campaigning to normalise conversations and get people to ‘Let’s #ChatMenopause’ and calling on employers to sign up to the Menopause Workplace Pledge.