Scientists isolate ovulation gene

Could mean breakthrough for infertility, contraceptive treatments

CAROLYN ABRAHAM

From Friday's Globe and Mail

Humans do it. Cows do it. Even Potbelly sows do it.

By the day, the month, or by the year (if you're a bear), all female mammals ovulate. Yet the release of the mighty egg, crucial to conception and survival of species, has been a biological mystery.

But scientists in Canada and France now say they have discovered a major gene that governs ovulation - a find that could yield new treatments for infertility and lead to a genetically based contraceptive.

In a study released yesterday, researchers report that deleting a gene, known as Lrh1, in the ovaries of specially bred mice completely blocked ovulation. It also upset hormone cycles, seemed to keep eggs from maturing and trapped them within the ovaries.

"This [gene] has a real shotgun effect," said senior investigator Bruce Murphy, director of the Animal Reproduction Research Centre at the University of Montreal. "Many more aspects and pathways are regulated by this gene than we ever thought."

Dr. Murphy, co-author of the report published in the current issue of Genes and Development, called it "a drugable gene" that could potentially be blocked to prevent conception and boosted to enhance fertility.

About 15 per cent of couples suffer from infertility, he said.

"Very frequently, this is due to ovulatory failure, and a lot of it cannot be explained. This is going to give us some clues to looking at unexplained infertility in women."

The researchers now plan to collect ovarian cells that would otherwise be discarded at fertility clinics and study whether the tissue carries a defective version of the Lrh1 gene.

Beverly Hanck, executive director of the Infertility Awareness Association of Canada, called the discovery "wonderful news."

"I'm dubious about any quick fixes," she said, "but it may be that women [who have faulty versions of the gene] can be identified early on, or can learn if they will have problems later."

Ms. Hanck estimated that about 330,000 Canadian couples suffer from infertility and for those who never have an explanation, "it leaves them shaking their heads ... wondering 'why me?' "

Scientists first found the Lrh1 gene in fruit flies in the early 1990s, then in mice and humans.

They initially thought it key to liver function and it earned its name as a "Liver receptor homolog" gene.

But five years ago, it caught the attention of the Montreal research group, which found Lrh1 to be highly expressed in the ovaries.

Working with colleagues at the Université Louis Pasteur in Strasbourg, Dr. Murphy and postdoctoral fellow Rajesha Duggavathi created a mouse model to study what role the Lrh1 gene might play in ovulation.

Women usually ovulate around the 14th day of a 28-day menstrual cycle. It starts with estrogen levels rising in the ovaries, Dr. Murphy explained.

The estrogen spike triggers the hypothalamus region of a woman's brain to signal the pituitary gland to pump out a luteinizing hormone.

Then, about 35 hours later, an ovarian follicle ruptures, releasing a mature egg as estrogen levels in the ovary drop and progesterone levels climb.

But researchers found that knocking out the Lrh1 gene kept estrogen levels high and stopped progesterone levels from surging. As well, the follicle never ruptured to release the egg. It also interfered with the important cells that typically surround a mature egg and enable sperm to fertilize it.

About 100 genes are suspected to play some role in the complex process of ovulation, Dr. Murphy said, but "this is a master gene that regulates lots of other genes."

While Lrh1 might also have its own master, he said, "we are very excited about it."

Roger Pierson, professor of obstetrics and gynecology at the University of Saskatchewan, called the report on the Lrh1 gene "absolutely significant."

How ovulation is regulated has been one of the "huge mysteries" in the field, he said and "this looks like a controlling gene."

"This is a very old, well-conserved [gene] for ovarian function in mammalian biology," Dr. Pierson said.

"Without this gene, the eggs would never get outside the ovary ... it's a very good target for understanding infertility and for safer, effective contraception."

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