A pea-sized gland and its fertility problem

By Deborah Oakley

Infertility is a more complex condition than had been thought, with more genes, and more types of genes, now known to play a role, says researcher Mathieu Latreille of the MRC Laboratory of Medical Sciences (LMS).

“Fertility problems have been studied for over one hundred years, but have yet to be fully understood. Now we’ve identified a new element in this complex story,” says Latreille. “Our study shows that mutations in a type of non-coding gene can cause infertility in mice, and we think that the same mutations may cause fertility problems in people too.”

In mice with the genetic mutation (right), the pituitary gland (blue) produces lower levels of reproductive hormones (green) than in healthy mice (left). The gland has two lobes either side of a midsection (red).

Genes typically contain the instructions or code that the cells in our bodies use to produce proteins, which are essential for cell structure and function. But in the 1990s, it was shown that not all genes produce proteins. Instead, these “non-coding” genes produce small molecules, called microRNAs. These molecules help to control and even block the activity of other genes by stopping them from producing proteins. This effectively turns genes off.

There are many different types of microRNA and early research has suggested that some may play a role in infertility. Latreille and colleagues are the first to show that a microRNA known as microRNA-7a2 is key.

Mice with an inactivating mutation in microRNA-7a2 develop unusually small ovaries and testes, and have low levels of reproductive hormones, shows the study. This includes luteinising hormone and follicle-stimulating hormone, which are together crucial for the healthy function of the reproductive organs. The male mice show impaired sperm production whilst the females cannot release eggs.

A similar mutation may underlie some infertility problems in people with no known cause, say the researchers, because the genes and hormones that control reproduction in mice are similar to those in people.

When the researchers mutated the gene that codes for microRNA-7a2, they observed changes in the mice’s pituitary gland. This is a pea-sized gland that sits in a bony hollow behind the bridge of the nose. It produces the reproductive hormones and plays a key role in the development of the sex organs.

The pituitary gland is linked with two other glands, called the hypothalamus and adrenal gland, in what is known as the HPA axis. It has been known that problems with this axis can lead to infertility. This study shows that a mutation in microRNA-7a2 can cause the pituitary gland to release lower levels of reproductive hormones than usual, and that this leads to infertility.

The study was published in the Journal of Clinical Investigation and co-led by Mathieu Latreille, who leads the Cellular Identity and Metabolism group at the LMS.

Read the paper here