The Case of the Missing Protein by Cate House

ometimes even when couples have good quality eggs and sperm, they still aren’t able to conceive. It may be that the woman has a condition, such as fluid-filled tubes or endometriosis, that prevents the embryo from attaching to the uterus.

But pinpointing the problem isn’t always easy. Take, for instance, the case of Sally and Carlos de Sousa. When they came to Carolina’s fertility clinic in 1994, they had been trying to conceive on their own for five years. After taking Clomed to aid with ovulation, undergoing artificial insemination, and having an exploratory laprascopy to try to figure out the problem, the de Sousas were referred to UNC-CH’s Assisted Reproductive Technologies (ART) program.

Doctors knew Sally de Sousa was infertile—they just weren’t sure why.

That can be frustrating for patients, says Bruce Lessey, associate professor of obstetrics and gynecology. “Patients find the diagnosis ‘unexplained infertility’ very difficult to comprehend, and they feel like it’s their fault for not being able to get pregnant.”

Lessey studies implantation—attachment of the embryo to the endometrium (the lining of the uterus). “We’re coming at infertility from the side of the maternal surface because up to two million women with unexplained infertility may have implantation failure,” he says. “If we can define the problems and how they arise, we should be able to help millions of couples avoid costly and sometimes painful therapies and allow them to conceive in a more natural way.”

n Sally’s case, Marc Fritz, chief of reproductive endocrinology, discovered that her fallopian tubes were blocked (filled with fluid), meaning that there was no egg movement to meet the sperm. To get around the problem, doctors performed in vitro fertilization (IVF), but after several attempts, including a couple frozen embryo transfers, she still wasn’t able to conceive.

The doctors thought the fluid in Sally’s fallopian tubes might be leaking into her uterus and flooding the embryos, so Fritz suggested taking her tubes out because the doctors were going to bypass them anyway with IVF.

While some women with fluid-filled tubes are able to become pregnant, studies have shown that, as a group, women with this condition have lower implantation and pregnancy rates. Lessey says the reason may have to do with certain proteins, known as integrins or cell adhesion molecules, that show up in the endometrium on the day the embryo attaches to the uterus. These are called “biomarkers” of uterine receptivity—signs that the uterus is ready for embryo attachment.

Lessey and his team of researchers found, for instance, that the biomarker alphav-beta3 was missing in women whose endometrium was developmentally delayed, maybe because they weren’t producing enough hormones or because their cycle was off. Interestingly, the biomarker was also absent in some women who appeared to have normal development of their endometrium.

“This was puzzling at first,” Lessey says, “but then we noticed that it was associated with very specific diagnoses.” In a study of women with fluid-filled tubes, for instance, Lessey and William Meyer, associate professor of obstetrics and gynecology, found that alphav-beta3 was often missing at the time implantation is supposed to occur.

his study suggests that major surgery to remove the tubes before doing IVF may not be necessary in every case, Lessey says. “If doctors are able to check the endometrium and see if alphav-beta3 is present, then they might be able to take out the tubes selectively in those patients who are missing the protein.”

After doctors removed Sally’s fallopian tubes, she eventually became pregnant. (She’s expecting twins in February 2001.) Because this research is so new, Sally wasn’t tested for the biomarker, but it’s likely that it wasn’t present until her tubes were removed. Lessey explains that sometimes conditions such as fluid-filled tubes mimic infections—they create inflammation, which is not a true infection—causing women to become infertile as a result.

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