Scientists at Stanford University and in Japan have developed an experimental technique to remedy one of the leading causes of female infertility. The findings, published in the journal PNAS, could pave the way for thousands of infertile women to become pregnant without an egg donor.

Primary ovarian failure (POF) affects nearly 250,000 women in the U.S. under the age of 40, and can trigger premature menopause as early as adolescence. The problem resides in a woman’s ovarian follicles, which typically grow one egg per month during one’s reproductive years from 15 to 44. In POF, the follicles never release an egg or do so irregularly, making pregnancy close to impossible for these women.

"Human females have about 800,000 very small, primordial follicles at birth, and one of these reaches maturity each month to produce an egg each menstrual cycle," said senior author Dr. Aaron Hsueh, professor of obstetrics and gynecology at Stanford. “It's not known exactly how the follicles are selected for development, or why these follicles stop developing in women with primary ovarian insufficiency. But our treatment was able to awaken some of the remaining primordial follicles and cause them to release eggs."

Until this study, there was no fertility treatment except for egg donation from another woman, but many sufferers yearn to have their own children.

To arouse the dormant follicles, the researchers turned to a surgical therapy for a different infertility condition — polycystic ovary syndrome. Since the 1930s, doctors have treated polycystic ovary syndrome by making small, internal cuts to the ovarian follicles. While damaging the follicles may seem counterintuitive, it works in some cases, although physicians have never understood why.

A scientist on Hsueh’s team, Dr. Yuan Cheng, discovered that a conserved network of enzymes — referred to as the Hippo pathway — was responsible for the beneficial effects of surgical treatment in a mouse model of polycystic ovary syndrome.

However, knowing this would not be enough to repair POF. Prior work in 2010 from the same group of scientists had isolated another enzyme — PTEN — as a possible mediator of ovary follicle growth. Drugs that blocked PTEN’s function were able to revive dormant follicles in mice and human ovaries growing in a Petri dish.

Hsueh’s team decided to combine both approaches — snip off a bit of the ovary from an infertile POF woman, treat those cells in dish with a PTEN blocker, and then implant them back into the original patient. The researchers dubbed this combined strategy “in vitro activation” (IVA).

To test their theory in humans, they collaborated with a group of obstetricians and gynecologists in Japan at the St. Marianna University School of Medicine.

Ovary follicle tissue was collected from 27 infertile women, 13 of which were suitable for IVA. The results were both astonishing and groundbreaking, with one woman giving birth to a healthy child.

"Although I believed, based on our previous research, that this IVA approach would work, I monitored the pregnancy closely and, when the baby was in a breech presentation, I performed the caesarean section myself," said Dr. Kazuhiro Kawamura, an associate professor of obstetrics and gynecology who led the team at St. Marianna.

"I could not sleep the night before the operation, but when I saw the healthy baby, my anxiety turned to delight. The couple and I hugged each other in tears. I hope that IVA will be able to help patients with primary ovarian insufficiency throughout the world."

Although another woman from the trial is also currently pregnant, it will take a much larger study to fully grasp the success rate of IVA.

The team plans to try IVA with other forms of infertility outside of POF, and they will search for drugs that directly target the Hippo and PTEN pathways in ovaries, with the hopes that the procedure could one day be conducted without surgery.

 

Source: Kawamura K, Cheng Y, Suzukia N, et al. Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment. PNAS. 2013.