Infertility Researchers Identify One Gene's Critical Role In The Human Embryo Implantation Process

"There have been studies done both in the United States and Europeshowing statistically that there is a defect in the implantationprocess in women with endometriosis, a condition affecting manypremenopausal women who also suffer from infertility," explainsLee-Chuan Kao, MD, PhD., a reproductive medicine specialist atCedars-Sinai and co-director of the hospital's Center for ReproductiveMedicine. "My interest was to determine exactly the molecular mechanismresponsible for implantation failure."

Endometriosis occurs when tissue similar to the lining insidethe uterus grows outside the uterus, usually on the surfaces of theovaries, fallopian tubes and other pelvic structures, making conceptionmore difficult.

Cedars-Sinai is one of less than a half-dozen facilities in the UnitedStates trying to dissect the mechanism of human embryo implantation andits link to endometriosis. In this recent study, Kao, working withMargareta Pisarska, MD, co-director of Cedars-Sinai's Center forReproductive Medicine, and Salma Khan, PhD, also of Cedars-Sinai,focused on one specific endometrial target gene (GlcNAc-6-OST) whichhas a role in shaping L-selectin ligand, a chemical responsible for thetethering and rolling mechanism described at the human maternal-fetalinterface, i.e. a signal that enables the embryo to recognize thelining of the endometrium.

"This gene (GlcNAc-6-OST) gets transcribed and then translated into aprotein and this particular protein functions as an enzyme," explainsKao. "It has been shown to be expressed specifically during the windowof implantation. My hypothesis is that this particular gene, for ayet-to-be-uncovered reason, is abnormally expressed in women withendometriosis which results in the embryo not being able to find theappropriate place to bind to the endometrium leading to a failure ordefect in the implantation process."

The in-vitro study tested whether ovarian hormones, estrogenand progesterone, can regulate the expression of GlcNAc-6-OST. Bytreating an endometrial cell line with the ovarian hormones, Kao andhis colleagues demonstrated that increasing estrogen during the firstpart of the menstrual cycle, when ovarian follicles mature to preparefor ovulation, increases the expression of the enzyme. After ovulation,progesterone production further heightens the expression of the enzyme.This up-regulation of the enzyme (when both estrogen and progesteroneare present) facilitates the production of L-selectin ligand whichenables implantation. When only progesterone was present withoutestrogen, the gene was suppressed and the endometrium would not bereceptive to implantation.

"Our next step," says Kao, "will be to explore other regulatorymechanisms or other chemicals - instead of hormones - that mightprovide us with a more specific approach to modulate this gene.Additional studies are required before we can apply this information toa clinical situation but I believe we've shown there is definitely aneed for more research."

One of only five hospitals inCalifornia whose nurses have been honored with the prestigious Magnetdesignation, Cedars-Sinai Medical Center is one of the largestnonprofit academic medical centers in the Western United States. For 17consecutive years, it has been named Los Angeles' most preferredhospital for all health needs in an independent survey of arearesidents. Cedars-Sinai is internationally renowned for its diagnosticand treatment capabilities and its broad spectrum of programs andservices, as well as breakthroughs in biomedical research andsuperlative medical education. It ranks among the top 10 non-universityhospitals in the nation for its research activities and was recentlyfully accredited by the Association for the Accreditation of HumanResearch Protection Programs, Inc. (AAHRPP). Additional information isavailable at www.cedars-sinai.edu.