UNDERSTANDING WOMEN'S HEALTH
Health issues that affect women's lives differently than men's are the focus of the newly formed Women's Health Research Institute of Amarillo.
Written by Erin Ritter and Michael Hughes
Suzanne Lindsey, Ph.D., was just entering her 30s when her mother died after battling endometrial cancer for nearly a decade. That event spurred a significant life change for Lindsey, who went back to college and now dedicates her career to cancer research.
She is a member of one of four research teams at Texas Tech University Health Sciences Center's schools of medicine and pharmacy in Amarillo that recently were awarded grants by the newly formed Women's Health Research Institute of Amarillo to study health issues that may affect women differently than men.
Lindsey, an assistant professor in the Department of Pharmaceutical Sciences at the Texas Tech School of Pharmacy, received a grant to study how metastatic cancers are signaled to spread from localized tumors to much more deadly malignancies growing throughout the body.
She and her research partner, Rusty Robinson, M.D., will study how activated proto-oncogenes signal ovarian cancer-specific cells to spread. A proto-oncogene is a normal cellular gene that is altered to become an active oncogene, that is, a gene capable of converting normal cells into cancer cells. Robinson is a gynecologic oncologist at the Harrington Cancer Center and an associate professor of obstetrics and gynecology at the School of Medicine at Amarillo.
Lindsey said she shares the vision of the Women's Health Research Institute's four founders: Steven Berk, M.D., regional dean of the Texas Tech School of Medicine at Amarillo; Arthur Nelson, Ph.D., dean of Texas Tech's School of Pharmacy in Amarillo; Joel Kupersmith, M.D., dean of the Texas Tech School of Medicine; and Moody L. Chisholm, chief executive officer of Northwest Texas Healthcare System in Amarillo.
"Having investigators from all of these institutions working together really strengthens our opportunity to become an important national center for research in women's health," Berk said. "One of the reasons we chose women's health as this focus for the School of Medicine's research was that we already had a good deal of expertise in women's health research on the campus."
Berk's hope is that the funded projects will result in abstracts, publications and possibly peer-review grants. He said attracting additional faculty whose interest is women's health is an important aspect of the research institute.
"We already have attracted two outstanding new faculty members whose careers have been in women's health research," he said. "Mark Arredondo, M.D., who is already here, was head of the breast cancer program at the Medical College of Ohio in Toledo. Joaquin Santolaya, M.D., has expertise in genetics and maternal fetal medicine, and he will be here this fall. These are examples of two individuals who are nationally known in women's health research and who were attracted to the Amarillo Medical Center partly because we have a Women's Health Research Institute."
Lindsey said she hopes eventually to devise a test allowing oncologists to study excised tumors to determine if the cancer already has spread elsewhere throughout the body. "Then you would have an idea whether or not to treat with something that would impair their migration."
Lindsey said she and Robinson eventually would like to help develop a method to block genetic messengers from broadcasting the signal for cancer to spread. Already, she has isolated two genes that are upregulated by a growth factor that has been shown to be expressed in most metastatic cancers.
Lindsey said her research could apply to 80 percent of the metastatic cancers: breast cancer, colon cancer, prostate cancer, squamous cell carcinoma, ovarian cancer, endometrial cancer and uterine cancer.
All this from a person who didn't decide she wanted to be a molecular biologist until her 30s.
"As a child, I loved science," she said. " When my mother died of cancer, it really spurred my interest. So, at the age of 37, I went back to school and did a full science undergraduate degree and a Ph.D. I think a lot of times people are pushed a little bit further when a loved one suffers from a certain disease."
An accident and an observation played a part in other researchers' interests in finding particular solutions to women's health problems. Thomas Myles, M.D., assistant professor of obstetrics and gynecology and director of maternal-fetal medicine at the School of Medicine in Amarillo, received a Women's Health Research Institute grant to study a new test that may help doctors diagnose gestational diabetes earlier in pregnancy.
Myles said gestational diabetes causes women a number of complications, including pre-term labor, high blood pressure, still birth, excessive fluid and large babies, and therefore, a resulting increase in the incidence of Cesarean-sections.
Women who develop diabetes during pregnancy have a 60 percent increased risk of developing full-blown diabetes later in life. Early diagnosis and treatment seems to reduce those risks, however techniques for early diagnosis are somewhat limited, Myles said.
"In general, diabetes is diagnosed at 24 or 28 weeks. But we'd like to be able to pick up gestational diabetes at less than 12 weeks so we could begin treatment much earlier," Myles said.
Standard procedure to diagnose gestational diabetes is glucose testing at 24 to 28 weeks.
Myles and his research partners, obstetrics/gynecology Professor Dan Castracane, Ph.D., and obstetrics/gynecology Chief Resident Amy Sarver, M.D., will test for insulin levels and the protein Inhibin A early in pregnancy on women who are at high risk for gestational diabetes.
"The hope is, that with the addition of insulin levels and Inhibin A levels, that we'll be able to make the diagnosis earlier," he said. "The preliminary evidence for Inhibin A seems to indicate that patients who go on to develop gestational diabetes do not have the same increase in Inhibin A levels that we see in a person who does not develop diabetes."
Insulin is a hormone produced by the pancreas to regulate blood sugar levels. Although Myles said women normally could become resistant to insulin during pregnancy, however women in danger from gestational diabetes may become resistant earlier. The researchers therefore will be testing insulin levels during the first trimester of pregnancy.
Inhibin A is a protein that's produced during pregnancy. And women who develop gestational diabetes seem to produce less of it. They have less of a peak in the level of Inhibin A during the first trimester of pregnancy, between eight and 10 weeks of gestation, Castracane said.
Castracane discovered the potential link between Inhibin A and diabetes by accident. He was studying a link between Downs Syndrome and Inhibin A levels, when a couple of patients who did not have the normal Inhibin A peak went on to develop gestational diabetes.
"The question is, is this something that's normal, or did it just happen with these few patients?" Myles wonders aloud. "Accidents happen. That's the way a lot of drugs are discovered in the first place and also the way off-label uses are found for medication."
The long-term effects of a common birth control method and cardiovascular risks in reproductive-age women are the interest of another researcher. John Jennings, M.D., received a Women's Health Research Institute grant to study the possible effects of the widely used birth control method, Depo Provera, on cardiovascular health in women as young as 16 to women in their 30s or 40s. Women throughout the world are using Depo Provera, but doctors still are learning about possible health risks related to this synthetic hormone, progesterone, said Jennings, regional chairperson of the Department of Obstetrics and Gynecology at the School of Medicine in Amarillo.
"The goal is to see whether a widely used medication like Depo Provera has a potential for long-term ill effects that previously were unrecognized in the hundreds of thousands of women who used it," Jennings said.
Jennings is collaborating on the study with Michael Hensley, M.D., instructor in the Department of Obstetrics and Gynecology. Jennings said some indicators show that there are differences in types of progesterone, synthetic and natural, and their effects on the cardiovascular system. These results have come from recent literature, primarily looking at postmenopausal women, and the use of different progestins, groups of hormones secreted by the corpus luteum and placenta, which induce the formation of a secretory endometrium.
"We want to study the effects of commonly used progestins on vascular reactivity (how blood vessels react) in young women. The Depo Provera, medroxyprogesterone acetate, (a type of progestin) has been approved for contraceptive use. It is widely used, yet no one really knows what the effect of that use might have on vascular reactivity," Jennings said.
Cardiovascular reactivity can be measured by ultrasound techniques and by a microvascular Doppler technique, an ultrasonic technique used to measure cardiovascular blood flow. The hardening of the arteries of cardiovascular disease begins early in life, even though the disease does not manifest in a cardiac event or a stroke until years later. Jennings said the pilot study that he and Hensley are conducting will compare three groups of women - one group receiving nothing, one group receiving natural progesterone, and the final group receiving synthetic progesterone. In the beginning, five women will be in each part of the study. Jennings expects the research to continue for several years.
He said some progestins cause a rise in conditions that cause inflammatory reaction in vessels that could create the conditions that result in heart attacks and strokes.
Depo Provera has been used for years for contraception and to control menstrual cycles. The researchers will look at the events that may start the process of heart disease early and measure and compare. For example, if researchers see that a woman who takes a medroxyprogesterone acetate has remarkably narrowed vessels and decreased blood flow to extremities compared to another woman who is taking a different type of progesterone or nothing at all, then the researchers will have a good indication that other adverse cardiovascular events may occur over a longer period of time.
The possible positive link between the hormone estrogen and Alzheimer's disease is what interests researcher James Stoll, Ph.D. He always has been intrigued by neuroscience. This curiosity led him to study the effects of Alzheimer's disease both at the National Institute on Aging in Bethesda, Md., and at the Texas Tech School of Pharmacy in Amarillo where he is an assistant professor of pharmaceutical sciences.
Stoll recently was awarded a grant from the Women's Health Research Institute to discover how estrogen may protect the brain from Alzheimer's, a disorder that gradually destroys a person's ability to reason, remember, imagine and learn, especially in older individuals.
In the United States, more than 4 million people have Alzheimer's disease, and women have a higher risk factor than men who are the same age do. Stoll's hypothesis is that estrogen acts to stimulate basal forebrain cholinergic neurons, and the activity of the high affinity choline transporter which transports choline from fluid outside cells that will be used to make acetylcholine, a neurotransmitter involved in learning and memory. Basal forebrain cholinergic neurons are severely diminished in the brains of Alzheimer's patients.
Once inside the cells, a second enzyme that controls the production of acetylcholine, choline acetyltransferase, uses the choline to make acetylcholine.
Estrogen can function in a different role than its conventional role as a sex, or reproductive, hormone. Stoll said the tie-in is that the risk of Alzheimer's disease appears to be greater in women with low postmenopausal estrogen level. He said it is possible that the low estrogen levels keep the basal forebrain neurons from carrying out their function.
"The important thing is that the transporter is the slow step in this process so by speeding up the transporter or by making more transporter, we can make more acetylcholine," Stoll said. "Speeding up choline acetyltransferase is not as effective because it already works faster. What we are going to do is test the hypothesis that estrogen stimulates the transporter."
Estrogen increases the synthesis of proteins. Stoll said the hormone also could increase the amount of transporter present in those cells. This will be easy to test, once and if, the hypothesis is proven.
Epidemiological evidence shows postmenopausal women with lower estrogen levels have a greater risk of developing Alzheimer's disease. Women who are on estrogen replacement therapy have a lesser risk of developing Alzheimer's disease.
"It appears in some form or fashion that estrogen is important in preventing Alzheimer's disease from occurring," Stoll said. "This grant is about testing one hypothesis of a biological mechanism through which estrogen is working."
If Stoll proves his hypothesis, he will be providing a reason for estrogen replacement therapy in postmenopausal women. The research also would identify new targets for treating Alzheimer's. Finally, understanding estrogen's mechanism of action allows drugs to be designed that mimic its therapeutic effects but do not have the undesirable side effects.
"Hopefully down the line we can harness those mechanisms to help regulate the activity in Alzheimer's patients," Stoll said.
Berk said he is pleased that the first group of Women's Health Research Institute grants included collaboration between the schools of medicine and pharmacy in Amarillo, but he hopes future grants also will include collaborating faculty from local undergraduate institutions that are represented on the institute's board and those at Amarillo College and West Texas A&M University.
The Women's Health Research Institute will bring the Texas Tech School of Medicine, the School of Pharmacy, Northwest Texas Hospital and the undergraduate schools together to develop research in all areas of women's health, Berk said. "Having investigators from all of these institutions working together really strengthens our opportunity to become an important national center for research in women's health."
The National Institute of Health now has a women's research division, and at least 10 other women's research institutes exist in the United States, including two in Texas, the Women's Health Research Institute in Amarillo and the Center for Women's Health at Baylor, he said. "There aren't many others in the western part of the United States. There may not be other medical schools where women's health is the focus of their research," he said. "Most of the academic medical centers that have women's health research institutes may have 10 other research institutes as well. Therefore Texas Tech is unique in choosing the focus of its research at this campus."
"Some people, when they think of women's health, think of issues of pregnancy, and that is very important. Some will think of diseases specific to women, and those are very important," Berk said. "But also equally important are issues of heart disease in women, stroke in women and hypertension in women and how they may be a little bit different. We need a new understanding of some of those issues specifically as they relate to women."
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