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A 29-year-old woman with primary ovarian insufficiency gave birth to a healthy boy after a novel technique induced her ovaries to produce eggs, researchers reported.
Another woman is pregnant and two others are in earlier stages of the process, according to Aaron Hsueh, PhD, of Stanford University in Stanford, Calif., and colleagues.
But only about a third of the 27 women in the study responded to the treatment, Hsueh and colleagues cautioned online in the Proceedings of the National Academy of Sciences.
In the U.S., primary ovarian insufficiency -- characterized by amenorrhea, low estrogen, and elevated serum gonadotropin in women younger than 40 -- affects about 1% of women and there is no effective treatment, the researchers noted.
On the other hand, in polycystic ovarian syndrome, which also causes infertility, disrupting ovarian tissue by mechanical means, such as ovarian "drilling" by diathermy or laser, can sometimes induce follicle growth and egg production.
Hsueh and colleagues in the U.S. and Japan found that a signaling pathway dubbed Hippo plays a key role in that process and hypothesized it might also be involved in primary ovarian insufficiency.
The Hippo pathway controls the growth of organs, ensuring they remain the right size for the body; in the ovary, the pathway appears to make sure that only a few follicles at a time are growing.
In animals, Hsueh and colleagues demonstrated that blocking Hippo in ovarian tissue could stimulate follicle growth.
To test the idea in humans, they enrolled 27 women in Japan, with an average age of 37, who had been amenorrheic for an average of 6.8 years when they joined the study.
The investigators removed their ovaries, using laparoscopic surgery, and cut them in strips. Analysis showed that 13 of the ovaries contained residual follicles.
Hsueh and colleagues treated those ovarian tissues with hormones to block the Hippo pathway and stimulate the growth of follicles, before re-implanting them beneath the serous membranes of Fallopian tubes.
In eight of the women, follicles grew and the researchers were able to retrieve eggs from five of them. Those eggs were fertilized with sperm from the women's partners and resulting four-cell embryos were transferred back into their uterus.
One woman received one embryo but failed to become pregnant, the researchers reported, while two other women are preparing for embryo transfer or undergoing additional rounds of egg collection. Another received one embryo and is pregnant.
And a 29-year-old woman, dubbed patient three, received two embryos, established a singleton pregnancy, and gave birth to a healthy boy, with a birth weight of 3,254 g and an Apgar score of 9 at 1 minute and 10 at 5 minutes. Delivery occurred after 37 weeks and 2 days of pregnancy.
"Our results obtained with our clinical collaborators in Japan make us hopeful that this is a group of patients who can be helped," Hsueh said in a statement.
"For patients with primary ovarian insufficiency, egg donation is the only option for bearing a baby," added Kazuhiro Kawamura, MD, PhD, of the St. Marianna University School of Medicine in Japan's Kanagawa prefecture.
Kawamura said he had been sure the procedure would work, but nevertheless, "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."
Despite the healthy birth, the investigators cautioned that more study is needed to ensure the safety of the process. And, they noted, not all women will be candidates for the process, because residual follicles have to be present for it to work.
The researchers had support from the National Institute of Child Health and Human Development, the California Institute of Regenerative Medicine, the Uehara Memorial Foundation, Naito Foundation, Terumo Life Science Foundation, Astellas Foundation, and the Mochida Memorial Foundation.
The journal said the authors declared they had no conflicts.
- Reviewed by Zalman S. Agus, MD Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner
Proceedings of the National Academy of SciencesSource Reference: Kawamura K, et al "Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment" PNAS 2013; DOI: 10.1073/pnas.1312830110.