Genetic finding provides insight into new cause of infertility

A European research collaboration has identified a new genetic cause for primary ovarian insufficiency, a condition that can lead to infertility in women.

Primary ovarian insufficiency - also known as premature ovarian failure - is characterised by the loss of normal function of the ovaries before the age of 40 years. It is a common condition, affecting around one in a hundred women. It can be caused by a number of factors, including autoimmune diseases, but in many cases the exact cause is unknown.

Scientists believe there is likely to be a genetic basis for the condition in some women, since a substantial minority of cases occur within families. However, so far, only rare genetic mutations have been identified, which cause only a minority of cases.

Now, research led by Dr Ken McElreavey and Dr Anu Bashamboo from the Institut Pasteur in Paris has identified mutations of a gene - known as NR5A1 - that are thought to be associated with primary ovarian insufficiency. The results are published today in the New England Journal of Medicine.

Studies in mice have shown that NR5A1 - also known as steroidogenic factor 1 - regulates the genes required for development of the sex organs. In particular, in females, it regulates function of the follicle, the structure in the ovary that contains the egg, and in males, development of the testes. It also regulates steroid production: oestrogen in females and testosterone in males.

The researchers studied four families with a history of ovarian deficiencies in the females and disorders of sex development in the males, as well as twenty-five girls or women with known ovarian insufficiency. The researchers found changes in the NR5A1 gene in all four families and in two of the twenty-five sporadic cases. These changes were not found in more than 700 controls (people with no reported ovarian or sex development disorders).

“We have shown that variations in this gene can be associated with loss of ovarian function,” says Dr John Achermann, a Wellcome Trust Senior Research Fellow at the Institute of Child Health, UCL (University College London), who collaborated in the study. “We know from animal studies that NR5A1 plays a key role in the development of the ovaries. Here, we have confirmed that the gene also plays an important role in humans.”

The researchers believe that the findings offer hope of developing a possible diagnostic test, particularly for women with a family history of premature ovarian failure. However, Dr Achermann stresses that this test is currently unlikely to be useful to women considering delaying pregnancy till later in life, as changes in this gene in the general population are likely to be rare.

“Even for women carrying an NR5A1 mutation, it does not necessarily mean that they will develop ovarian insufficiency later in life, and nor does it tell us when this may occur,” he says. “More research is needed to answer these questions, but this study is an important step towards understanding how ovaries and testes develop and function. and also how some forms of primary ovarian insufficiency arise.”

The research was supported by the Agence Nationale de la Recherche-GIS Institut des Maladies Rares, the March of Dimes Foundation, the National Institute for Health Research Biomedical Research Centre and the Wellcome Trust.

Notes for editors

1. Lourenço D et al. Mutations in NR5A1 Associated with Ovarian Insufficiency. New England Journal of Medicine, 26 February 2009.

2. The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research, in the UK and internationally, spending over £600 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing.

3. UCL (University College London) Founded in 1826, UCL was the first English university established after Oxford and Cambridge, the first to admit students regardless of race, class, religion or gender, and the first to provide systematic teaching of law, architecture and medicine. UCL is the seventh-ranked university in the 2008 THES-QS World University Rankings, and the third-ranked UK university in the 2008 league table of the top 500 world universities produced by the Shanghai Jiao Tong University. UCL alumni include Marie Stopes, Jonathan Dimbleby, Lord Woolf, Alexander Graham Bell, and members of the band Coldplay. UCL currently has over 12 000 undergraduate and 8000 postgraduate students. Its annual income is over £600 million.