Predicting which women will respond to fertility medications isn't always an absolute science. But now a new study from the National Institutes of Health implies that doctors may be able to determine response to these drugs based on whether or not their female patients carry an estrogen-based gene or not.1
The Genetic Connection?
The gene is known as estrogen receptor beta (ER beta), one of two estrogen receptor proteins that boost the effect of estrogen hormones in the body. The study by doctors at the National Institute of Environmental Health Sciences (NIEHS) used mice to determine if an abnormality in the gene affects ovulation.
"What we found is that the beta estrogen receptor plays a role in moving the egg outside the ovary so it can be fertilized," explained Kenneth Korach, PhD, a NIEHS laboratory chief, who led this study. "We never knew before what function this receptor played in reproduction."
The findings suggest that the gene has a significant part in the processes leading to ovulation, and may mean that women who don't possess it could benefit from alternative infertility therapy, the researchers note.
"The tools and animal models necessary to do these types of studies have only recently become available, but are already helping us to better understand the role of estrogen in the ovary," explained John Couse, PhD, lead author of the Endocrinology paper.
Missing Gene May be Responsible
Estrogen receptor beta was first discovered nearly a decade ago, and it was found that it plays a key role in ovarian function.2 Scientists have been attempting to determine if the subfertility they were seeing in animals might be the result of a missing ER beta gene, Korach told Priority Healthcare. "What we have been doing for the last several years now has been trying to understand exactly where the problem is, and testing whether, in fact, it really is the loss of ER beta that is producing this effect," he said.
"It appears that ER beta is involved in mediating some of the aspects of the ovulatory stimulus and responsiveness," Korach added.
To determine the role of the gene on the effects of ovulation stimulating drugs, Korach and his team gave medications similar to those given to women undergoing ovulation induction to two separate groups of mice. One group consisted of normal mice with the gene, and the second included rodents that were bred to lack estrogen receptor beta.
The mice without the gene were more likely to be infertile and produced fewer offspring, compared to the animals with estrogen receptor beta, Korach's group learned. Fewer pregnancies were seen in the rodents that lacked the gene, as well, the researchers found. And treating the mice with ovulation drugs didn't improve outcomes. The researchers found that the without the gene, the follicles in the animals were unable to release eggs.
This research expanded on an earlier NIH study involving a lab experiment in which scientists scrutinized the role of estrogen receptor beta in the ovulation process.3
The researchers in that study found that ovaries that lacked the gene had poor follicle growth, released less estrogen—needed in the processes leading from ovulation, through fertilization, and the embryo's implantation in the uterus—and had reduced ovulation. "Estrogen receptor beta appears to facilitate follicle maturation," the study authors wrote.
Hormones May Not Help
Korach and his colleagues theorize that in animals (and possibly humans) lacking the gene, even a surge of reproductive hormones produced by the body, such as luteinizing hormone (LH), which normally prompts a follicle to release an egg, may not be able to prompt ovulation. "That is now the current hypothesis that we would like to further evaluate," said Korach.
In fact, the missing gene may be the culprit in cases in which women who aren't responding to fertility medications can't be otherwise explained, he speculated. While findings in animals don't always perfectly translate to humans, the researchers in this study hope to expand on their results by analyzing the role of the receptor in women already undergoing fertility therapy.
Inheritance or Environment?
It's not known why some women lack this gene and others do not. It may be inherited or due to some environmental defect that alters the gene's function, which results in ovulation difficulties, the NIH scientists state. Estrogen receptor beta is also known to respond to various environmental and dietary chemicals that can mimic the effects of estrogen and stimulate the body's natural hormones. One example is genistein, a common component of soy products.
If future studies in women confirm the findings of this animal study, the researchers say a simple blood test could be used to determine whether some abnormality may be altering the function of the gene in certain women.
"Obviously, we still need to evaluate where the ER beta activity is, understand what it's doing in the follicles, then try to see if there's some way to circumvent that loss of activity, and then produce an adjuvant therapy that could be used," said Korach.
1. Couse JF, Yates MM, Deroo BJ, Korach KS. Estrogen receptor-{beta} is critical to granulosa cell differentiation and the ovulatory response to gonadotropins. Endocrinology 2005 Aug;146(8):3247-62. Epub 2005 Apr 14.
2. Mosselman S, Polman J, Dijkema R. ER beta: identification and characterization of a novel human estrogen receptor. FEBS Lett 1996 Aug 19;392(1):49-53.
3. Emmen JM, Couse JF, Elmore SA, Yates MM, Kissling GE, Korach KS. In vitro growth and ovulation of follicles from ovaries of estrogen receptor (ER){alpha} and ER{beta} null mice indicate a role for ER{beta} in follicular maturation. Endocrinology 2005 Jun;146(6):2817-26. Epub 2005 Feb 24.
John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include overseeing health news coverage for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.
