The Register Citizen (Torrington, CT)
Doctor targets uterine disease
NEW HAVEN — While the cause of endometriosis remains a mystery, Dr. Valerie Flores is intent on reducing the pain women suffer by helping identify the best treatment for each patient.
Endometriosis is related to menstruation, when the lining of the uterus, the endometrium, sloughs off each month during a woman’s menstrual cycle. The disease occurs because of “retrograde menstruation, where the tissue, instead of going out (through the vagina), ends up going out through the fallopian tubes and then implants into the pelvis,” said Flores, a fellow in the Yale School of Medicine’s Department of Obstetrics, Gynecology and Reproductive Sciences.
The tissue attaches to nearby organs, including the uterus, the ovaries or the peritoneum, a membrane that lines the abdominal cavity.
“The issue is that, because that tissue isn’t supposed to be there, it causes a kind of an inflammatory response,” she said.
“Just like the endometrium, it’s endometrial tissue that grows in response to hormones and causes pain and can cause infertility.”
What Flores is focused on is the ability to determine the best therapy for an individual woman’s disease, based on how her cells respond to the hormones estrogen and progesterone.
Estrogen promotes the growth of the endometrial tissue, while progesterone acts as a brake on estrogen. However, Flores believes that the standard therapy of giving patients drugs with progesterone, such as birth control pills, does not help every patient. She wants to target therapy to each woman by examining the lesion on the molecular level to determine whether a patient has a high or low number of progesterone receptors.
“The worst thing to me is you have a patient who you automatically give them birth control pills and it takes four to six weeks to take effect … and they’re suffering for four to six weeks.”
Meanwhile, the treatment doesn’t help, Flores said.
Flores’ work has gotten noticed by the Society of Reproductive Investigation, which, supported by the pharmaceutical giant Bayer, awarded her one of seven $15,000 grants to launch the SRI and Bayer Discovery/ Innovation Grants program.
About 10 percent of women suffer from endometriosis during their reproductive years.
“It’s been recognized for over 100 years and remains poorly understood,” Flores said. “There are so many factors that play into the disease.”
Treating each patient
In addition to intense pain, it can make a woman infertile, although why that is so is not clear. The lesion “can block where the egg needs to go, which is through the fallopian tubes, (or) the environment itself might not be the best for an egg,” she said.
Current practice is to remove the endometrial lesion through laparoscopic surgery, then to give medications with progesterone, such as oral contraceptives.
“Right now we do treat it with a progesterone therapy and if it doesn’t work we move on to other therapies,” Flores said. “No one’s bypassed that to say, ‘Let’s look at that from an individual point of view’” and tailor the treatment to the patient.
The problem is that endometriosis lesions have a wide variation in the number of progesterone receptors in their cells. If there is a low number of receptors, progesterone won’t be effective.
“We know that some patients can be progesterone-resistant and we think that it’s because the progesterone receptor is low. That’s what I’m trying to prove,” Flores said.
“I’m also just trying to say that we shouldn’t just give someone a particular therapy. … I want to know right off the bat what their molecular markers are so that I can treat them more effectively.”
Flores said that, without examining the lesion on the molecular level, “you don’t know which patient is going to be resistant to progesterone and which isn’t.” She wants to “avoid this guessing game and avoid them suffering with a medication that’s not going to work.”
When a patient’s lesion is low in progesterone receptors, “we have other medications that can block or lower estrogen production.” For example, Lupron Depot (the trade name for leuprolide acetate) suppresses the production of estrogen, which is what promotes growth of the endometriosis lesion.
Another aspect of Flores’ research is in determining more exactly what is considered a high or low level of progesterone receptors, using a scoring system used by pathologists.
The amount of estrogen a woman’s body produces does not determine whether or not she will get endometriosis. “The levels of hormone in women with endometriosis and the women without endometriosis are the same,” Flores said. “It’s really at the molecular level that there are differences in terms of receptor status.”
Another challenge is that “the disease is so heterogeneous; there’s no one-sizefits-all,” Flores said. “A lot of women have retrograde menstruation but not everyone gets endometriosis. While we’re still working on trying to find the ‘why,’ in the meantime, if we can minimize patients’ suffering, I think that’s huge.”
In need of attention
Sandra Davidge, who was president of the Society of Reproductive Investigation when Flores was chosen for the grant, said, “It’s an international review process and international competition, so it shows excellence of research for her to be chosen. SRI is based in Milwaukee.
Bayer provides the grant money, but SRI’s grants committee determined who would receive the awards. “We have the membership, we have the research excellence, we have the peerreview process,” Davidge said.
Chandra Ramanathan, who is a vice president of Bayer and head of its East Coast Innovation Center in Boston, said, “What we are hoping is we have identified areas of reproductive health that need the most attention.”
Bayer hopes the researchers in three areas, endometriosis, uterine fibroids and polycystic ovarian syndrome, will help the company develop new drugs to treat those conditions.
“Our goal is to build a network across the U.S. to identify and support the best innovators in the field,” Ramanathan said.
Flores works in the lab of Dr. Hugh Taylor, chairman of the Obstetrics, Gynecology and Reproductive Sciences Department and chief of obstetrics and gynecology at Yale New Haven Hospital. He is also editor in chief of SRI’s online journal, Reproductive Sciences.
“I feel truly blessed and honored to have this opportunity,” Flores said of the SRI-Bayer grant.
“This disease can be really debilitating for women, and if there’s any way I can end their suffering through my research and through this grant then it’s something I feel truly honored to be a part of.”