October 2, 2013
Breakthrough Infertility Treatment Induces Egg Growth In Sterile Women
[ Watch The Video: Inducing Egg Production In Infertile Women ]
Rebekah Eliason for redOrbit.com – Your Universe OnlineMany women experience the devastating reality of infertility at a young age, but new research offers hope for women with conditions such as primary ovarian insufficiency.
Researchers in Kawasaki, Japan from St. Marianna University School of Medicine used a method developed at Stanford University to collect mature eggs from women with primary ovarian insufficiency. One of the women treated is now pregnant and another recently delivered a healthy baby.
The experimental study was conducted in Japan and included twenty-seven participants. Five of the women produced viable eggs that were collected for in vitro fertilization. This technique has not been studied in other cases of infertility, but researchers intend to test its effectiveness on women who experience early menopause due to cancer and radiation as well as infertile woman between the ages of forty and forty-five.
This new treatment technique has been dubbed “in vitro activation” (IVA) and involves removing the ovaries to treat them while outside of the body. Once treated, they are re-implanted close to the fallopian tubes, and hormones are taken by the woman to induce the growth of specialized follicles. It is within these follicles that eggs develop.
Aaron Hsueh, professor of obstetrics and gynecology at Stanford and senior author of the study said: “Women with primary ovarian insufficiency enter menopause quite early in life, before they turn 40. Previous research has suggested that these women still have very tiny, primordial primary and secondary follicles, and that even though they are no longer having menstrual cycles they may still be treatable. Our results obtained with our clinical collaborators in Japan make us hopeful that this is a group of patients who can be helped.”
THE ORIGINS OF PRIMARY OVARIAN INSUFFICIENCY
When a baby girl is born, her ovaries already contain thousands of primordial follicles, each containing a single immature egg. In a normal menstrual cycle, only one egg develops to maturity each month to be released into the fallopian tubes. In the United States, approximately 1 percent of reproductive age women have the condition primary ovarian insufficiency, which means they do not produce normal estrogen amounts or regularly release eggs.
Since women have a limited number of eggs, most follicles will stay dormant for years in order to preserve her supply. Dr. Hsueh previously studied a signaling path which contains several proteins, notably PTEN, that is responsible for controlling follicle growth and egg development. He was able to show that blocking the PTEN protein in the ovaries of mice and humans was sufficient to stimulate follicle growth. This new study built on the findings of Dr. Hsueh.
Kazuhiro Kawamura, MD, PhD, associate professor of obstetrics and gynecology at the St. Marianna University School of Medicine led the clinical side of the research and is also the lead author of the paper.
“For patients with primary ovarian insufficiency, egg donation is the only option for bearing a baby,” Kawamura said. “These patients are eager to find a way to become pregnant with their own eggs. I have collaborated with Dr. Hsueh since 2010, working on ways to wake up these dormant follicles. When I was successful in obtaining mature human eggs from large, developed follicles after blocking PTEN activity, I gained confidence that this approach could work clinically.”
Valerie Baker, MD, associate professor of obstetrics and gynecology, chief of Stanford's division of reproductive endocrinology and infertility and the director of Stanford's Program for Primary Ovarian Insufficiency was not involved in this study but is currently collaborating with Dr. Hsueh to continue investigating the experimental treatment.
Baker commented that: “Although there are too little data available about this experimental treatment to guarantee any kind of success rate, the approach does look quite promising for women who have run out of eggs.”
The birth resulting from this study used two treatments that have been known to cause follicle growth. For years it has been accepted treatment for polycystic ovary syndrome to disrupt ovaries by cutting or drilling small holes to stimulate follicle growth, but up until recently it has been a mystery as to why exactly this works.
A NEW HOPE
The mystery was solved by Yuan Cheng, PhD, a postdoctoral scholar working in Hsueh’s lab. He was able to show that when the ovaries are cut, a growth arrest pathway called Hippo is disrupted. Originally, the Hippo was discovered in flies, but several animals share the Hippo pathway. In many animals the Hippo controls the growth of organs to ensure that they stay the right size. It also serves to regulate follicle growth in the ovaries to ensure conservation of the egg supply.
Dr. Hsueh, along with his colleagues, began wondering if combining both disruption to the Hippo path and inhibition of the PTEN pathway would work together to stimulate follicle growth. Through experiments with mice and humans it was determined that the two methods have an additive effect with each other. The two treatments together were able to stimulate more follicles than either treatment type alone.
“Human females have about 800,000 very small, primordial follicles at birth,” Hsueh said. “Most of them remain dormant, and only about 1,000 start to grow each month. One of these reaches maturity each month to produce an egg each menstrual cycle. 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.”
In this recent study, 27 women who had an average age of 37 years and had stopped menstruation an average of 6.8 years earlier were selected to participate. Thirteen of the women treated were found to have ovaries with residual follicles.
The first step was to mechanically fragment each woman’s ovaries and treat them with drugs that blocked the PTEN pathway. Each woman then had small pieces of her treated ovary laproscopically transplanted near her fallopian tubes. Follicle growth was determined by hormone-level tests, and weekly or biweekly ultrasounds were performed.
In eight of the women, follicle growth was detected. Of the eight, all were treated with hormones to induce ovulation and five went on to produce mature eggs. The eggs were then removed from the women and fertilized with their partner’s sperm. The results produced four embryo cells which were frozen and placed in the uterus.
One woman failed to become pregnant after transfer. Another woman is currently pregnant. A third woman conceived and gave birth to a boy and two other women are preparing for transfer or are undergoing additional rounds of egg collection.
“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 Kawamura. “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.”
In the future, Dr. Hsueh and other researchers intend to study women who are infertile for other reasons. Hsueh also would like to find a method that can use drugs alone without employing the invasive removal of ovaries.
Baker said, “When I first saw the data, my eyes lit up. These women and their partners come to me in tears. To suddenly learn at a young age that your childbearing potential is gone is very difficult. This technique could potentially help women who have lost their egg supply for any reason.”