Inside research

Designed for women: research in women’s health

by Sathya Achia Abraham, Malorie Janis, Anne Buckley, Mike Porter

Women's faces of varying age and race

For years, physicians have treated women with cardiovascular disease, rheumatologic, immunologic or psychiatric disorders and sexual dysfunction with the same arsenal of treatments, therapies or management as they have treated men.

Not bad for equality; however, basic and clinical researchers have now discovered a variety of differences that exist between the sexes in terms of pathology and susceptibility to particular diseases and conditions. Take heart disease, for example, which now ranks as the No. 1 killer of American women.

Previously health studies followed solely male subjects, but the findings that were reported did not serve both populations effectively because, in most cases, women and minorities were left out of the equation.

Only in the past 15 years has the research establishment shifted gears to develop studies that focus on diseases or conditions that are most prevalent among women and uncover the therapeutic options that work best for them.

At Virginia Commonwealth University, a national leader in women’s health research, experts are exploring all facets of research that affect women across the lifespan through basic, preventive, clinical and applied research.

Women’s health researchers are collaborating across VCU’s campuses to improve prenatal awareness and infant mortality rates among disparate populations; uncover the genetic risks linked to preterm birth; investigate how the mental health needs differ between women and men; and understand how “mind-body-spirit” interventions can help breast cancer patients cope with illness, heal the soul and improve quality of life.

“We have a wonderful working relationship between basic sciences in all disciplines in the School of Medicine and the other health science schools at our medical center. I can’t say enough about that because women’s health research is multidisciplinary,” said Jerome F. Strauss III, M.D., Ph.D., dean of the VCU School of Medicine.

“The ability to work with colleagues in the School of Dentistry, School of Pharmacy, School of Nursing and also colleagues on our main campus — in psychology, for example — has made it possible for us to do things that are truly exceptional, things that couldn’t be done at institutions that don’t have the breadth of expertise that we are fortunate to have at VCU.

“Our relationship between scientists and clinicians is also very special,” he said. “We have lab scientists working hand-in-hand with clinicians to find solutions to important problems in women’s health. This is done seamlessly so that basic science concepts can be brought to a clinical test and hopefully on to application.”

Genetic link to preterm birth

Jerome F. Strauss III, M.D.

Prematurity has become an epidemic in the U.S., where one in 10 pregnancies is complicated by the condition. Preterm birth is common, costly and frequently fatal. Researchers and policy makers are learning that it also has all the makings of a major public health problem.

Further, the ethnic disparity involved with premature births presents a significant concern. African-Americans experience adverse pregnancy outcomes much more frequently than whites, resulting in infant death rates that are more than twice those of the white population.

Through an aggressive research initiative, Strauss has made it a priority to make a change.

“To understand the basis of this disparity, which is related to population access to care and potentially to environmental factors, researchers have a substantial amount of work ahead of them,” Strauss said.

“We sorely need improved predictive measures so that therapeutic interventions can be implemented for appropriate patient populations,” he added.

According to Strauss, preterm premature rupture of membranes, PPROM, is the leading identifiable cause of preterm birth and leads to early delivery in 80 percent of cases. He said that PPROM is associated with an ethnic disparity where non-whites and African-American women are more likely to present with PPROM compared with Caucasian women.

Assessing a woman’s risk for preterm birth is a major issue as there are “no screening tests to predict preterm labor with significant positive predictive value,” Strauss explained.

In the past 10 to 15 years, investigating how genetic factors contribute to preterm birth has become a major area of research.

Two years ago, Strauss led a study that identified a genetic variant that may account for the higher rates of premature delivery experienced by African-American women compared with European-American women.

The findings, published in the Proceedings of the National Academy of Sciences, may help physicians identify patients who could benefit from therapeutic interventions and preventive measures, including lifestyle change or medical therapy to reduce the risk of premature birth.

“Our discovery of an association between a gene variation that is more common in individuals of African descent and a cause of premature birth, may explain in part the disparity in prematurity rates in African-Americans,” said Strauss. 

“More importantly, the genetic signature can help us identify women at risk of early breakage of the ‘bag of waters’ so that appropriate monitoring and therapy can be applied in order to prevent this serious pregnancy complication.”

The team found that a change in a single nucleotide in the gene sequence — known as a single nucleotide polymorphism — in the SERPINH1 gene may be responsible for the increased risk of PPROM in women of African descent. The SERPINH1 gene encodes a heat shock protein known as Hsp47, which is essential for collagen production. Collagen lends strength to the membranes that surround the fetus and amniotic fluid.

When this gene is expressed at a lower level than normal, and thus the collagen in the membranes experience reduced production, it results in weaker fetal membranes, making them more prone to rupture. Other published research has reported that reduced collagen content has been found in PPROM fetal membranes. This work was supported in part by grants from the National Institute of Child Health and Human Development and the March of Dimes Foundation.

“The gene we have discovered is only one of probably a handful of other genes that contribute overall to the risk of preterm births so we are continuing our studies to determine the full menu of potential genetic risk factors,” Strauss said.

“Ideally we would like to have a simple test available to couples. Prematurity also affects other ethnic groups and it would help if we could offer this as a screening tool to help obstetricians monitor and manage their patients so they can reduce the risk of prematurity overall.”

Pregnancy outcomes and health disparities

In other work, Strauss is leading a multidiciplinary research team at the VCU Center on Health Disparities to examine adverse pregnancy outcomes in African-Americans and potential interventions to prevent them. They will also identify ways to increase prenatal awareness and reduce infant mortality.

“This research program addresses a major unmet need in the United States and the commonwealth of Virginia. In developing new ways to ensure healthy pregnancies with healthy outcomes, we will have a major impact on the cost of health care and, in the long term, reduce the burden of chronic diseases that have their roots in pregnancy complications,” said Strauss, who is the primary investigator for the project.

Through a National Institutes of Health grant totaling nearly $6.4 million, they will initiate three research projects that will focus on varying aspects of health disparities. They will further investigate the genetics of preterm birth in African-Americans, immunological responses to periodontitis that may lead to premature birth, and ways to increase safe-sex awareness skills among pregnant women at high risk for HIV infection.

Additionally there will be two pilot projects that will aim to enhance fetal exposure to antiretroviral medications and to examine the geographic distribution of birth outcomes and environmental stressors.

They hope these findings will help researchers identify and implement new diagnostic tools and interventions that will address major health disparities.

Furthermore, Strauss said that the center will also provide research training opportunities for disparity population students. The grant designates funds for students from Virginia Union University, a historically black university in Richmond, to work with investigators through the health education intervention and other research projects.

Treating polycystic ovary syndrome

John Nestler, M.D.

For more than 20 years, John Nestler, M.D., vice chair of the Department of Internal Medicine and chair of the Division of Endocrinology and Metabolism at the VCU School of Medicine, has been studying the effects of insulin on polycystic ovary syndrome, PCOS, a disorder of the endocrine system that affects as many as 5 million women and is a leading cause of infertility in American women.

PCOS causes hormonal imbalances leading to irregular menstrual cycles, excess facial and body hair, weight gain and adult acne. Women with PCOS are at high risk for developing Type 2 diabetes and are also at increased risk for cardiovascular disease. 
 
In the 1980s, Nestler was among the first scientists in the world to suggest that insulin was an important reproductive hormone. His pioneering work to induce ovulation through the use of such insulin-sensitizing drugs as metformin has led to the common use of metformin to treat infertility in women with PCOS. In a 1998 article in the New England Journal of Medicine, Nestler's research team was the first to publish findings on the combination therapy of metformin and clomiphene, an ovulation-stimulating drug, to promote ovulation.

Nestler recently authored a review published in the New England Journal of Medicine offering physicians improved treatment guidelines for women with PCOS. In the review, Nestler highlighted a case study of a 23-year-old-woman with PCOS and discussed the use of metformin for the treatment of PCOS and outlined its benefits, side effects and areas of uncertainty.

“Over the past 10 years, the long-term treatment of PCOS has changed considerably with appreciation of the disorder’s association with insulin resistance and substantial long-term metabolic risks,” Nestler said.

“Treatment with metformin often addresses not only the traditional goals of therapy, such as amelioration of irregular menstrual cycles and signs of androgen excess, but also the new goals of retarding progression to Type 2 diabetes and early cardiovascular disease,” he said.

PCOS and pregnancy

In a 2007 study published in the New England Journal of Medicine, Nestler along with Penn State College of Medicine colleague Richard S. Legro, M.D., examined the best pharmacological means for a woman with PCOS to achieve pregnancy and to determine the rates for live births.

They found that when time is of the essence, clomiphene may be superior to metformin in achieving live births in women with PCOS. They also observed that when metformin was added to clomiphene, the number of ovulations increased, compared to clomiphene alone. However, they did not observe an increase in the number of live births.

“Our findings underscore the usefulness of clomiphene in women who want to become pregnant quickly. However, metformin remains useful in fertility — especially in women who want to avoid multiple pregnancies and where time is not of the essence. Also, metformin still plays a role in long-term management of women with PCOS and may prevent progression to diabetes or heart disease,” he said.

The National Institutes of Health-funded study followed approximately 630 infertile women with PCOS at 13 medical centers across the country, including the VCU Medical Center. The participants were randomly assigned to one of three treatment groups, including clomiphene citrate plus placebo, extended-release metformin plus placebo, or a combination of metformin and clomiphene. Once a pregnancy was confirmed, the participants stopped drug therapy and researchers followed their progress until delivery.

According to Nestler, clomiphene induces an ovulation more quickly than metformin. However, he said that when using clomiphene there is an increased risk — approximately 4 percent to 6 percent — of having twins or triplets. Researchers observed that in the two arms of the study that contained clomiphene, there were multiple births, however in the arm that contained only metformin, there were no multiple births.

Clomiphene has been the standard therapy for women who do not ovulate. Previous studies done by Nestler, as well as by other researchers, have shown that adding metformin to clomiphene can dramatically increase the number of ovulations that a woman has compared to clomiphene alone.

Women’s mental health

Susan Kornstein, M.D.
  Susan G. Kornstein, M.D.

More than 20 percent of women will experience depression at some point in their lives — it is about twice as common in women as in men. The risk for depression in women is highest during the childbearing years and researchers are learning that not only biological factors, but also social and cultural influences, impact a women’s mental health and well-being.

Susan G. Kornstein, M.D., an internationally recognized researcher in women’s mental health and depression at VCU, has been making great strides in understanding how depression impacts the lives of women across the life span, as well as the influence of the menstrual cycle, pregnancy, the postpartum period and menopause on depression and its treatment.

“In recent years, we have learned a great deal about how depression affects women. And we’ve learned there are important differences when evaluating and treating depressed women compared to depressed men,” said Kornstein, co-founder and executive director of the VCU Institute for Women's Health, a designated National Center of Excellence in Women’s Health. She is also director of clinical research for VCU’s Department of Psychiatry and executive director of the VCU Mood Disorders Institute.

Premenstrual worsening of depression

According to findings of a 2005 study led by Kornstein, women with depression commonly report fluctuations in their symptoms across the menstrual cycle — a key factor that may help physicians better evaluate and treat depressed women.

Of 433 premenopausal women with major depressive disorder, 64 percent reported a worsening of their depression in the five to 10 days prior to menses. Women reporting premenstrual exacerbation, PME, of symptoms were compared with those reporting no PME with regard to a number of characteristics.

The women in the study were participants in a larger study funded by the National Institute of Mental Health called the Sequenced Treatment Alternatives to Relieve Depression or STAR*D study. VCU is one of several regional centers around the United States involved in the STAR*D study and Kornstein is the principal investigator for the study at VCU.

Kornstein, a professor of psychiatry and obstetrics and gynecology in VCU’s School of Medicine, said STAR*D researchers have collected data from more than 4,000 participants and are conducting several sub-studies and sub-analyses in various mental health areas.

Kornstein is taking a leading role in analyzing the effects of gender and menopausal status on depression presentation and treatment response. Her groundbreaking study in 2000 on gender differences in antidepressant treatment response drew international attention and has become one of the most-referenced articles in the psychiatric literature.

“The STAR*D study is helping to set the standards of how we treat depression,” Kornstein said. “Most doctors are unaware that the symptoms of depression can differ in women and men, or that depression in women can fluctuate with the menstrual cycle.”

Kornstein is now serving as principal investigator for the VCU site of the National Institutes of Health Depression Trials Network, which is conducting innovative depression research in 14 centers across the U.S.

Help for women with moderate-to-severe PMS

Up to 60 percent of women suffer from PMS, while only about 5 percent suffer from premenstrual dysphoric disorder, PMDD, a severe form of premenstrual syndrome. PMS symptoms may include irritability, depressed mood, anxiety and mood swings, along with physical symptoms such as bloating and breast tenderness. PMDD is characterized by severe mood symptoms that interfere with function.

In 2006, Kornstein led the first study to evaluate the use of low-dose antidepressant medication for women with moderate-to-severe PMS and found that these women may benefit from treatment with low doses of the antidepressant medication sertraline taken for two weeks before the onset of the menstrual period. Sertraline is a selective serotonin reuptake inhibitor approved for the treatment of depression and anxiety, as well as for PMDD.

The study team also tested and found two other antidepressant dosing strategies to be effective. One of those dosing strategies was taking medication daily throughout the menstrual cycle. The other was waiting until PMS symptoms begin to start medication each cycle, which is known as ‘symptom-onset’ dosing.

Kornstein and her colleagues evaluated approximately 300 women with PMS from 22 sites throughout the U.S. The participants were randomly assigned to fixed-dose treatment with 25 or 50 mg of sertraline or a placebo for four menstrual cycles. She collaborated with researchers from Brown University School of Medicine and Pfizer, Inc., which funded the work.

Recently, recruitment of participants began for a national study, sponsored by the National Institute of Mental Health, to further examine ‘symptom-onset’ dosing of an antidepressant for PMDD. Kornstein is the principal investigator at VCU. Subjects will take sertraline or a placebo at the onset of symptoms each menstrual cycle for six months. The goal is to enroll 300 women among three sites — at Yale University, Cornell University and VCU.

Living with incontinence

Catherine A. Matthews, M.D.

Through research, clinical expertise and teaching, Catherine A. Matthews, M.D., associate professor of obstetrics and gynecology in the VCU School of Medicine, helps thousands of women who suffer from incontinence manage this distressing and isolating condition, which can take a tremendous toll on quality of life.

Incontinence — urinary or bowel — occurs in up to 30 percent of women and can be a consequence of childbirth or aging. According to Matthews, who specializes in urogynecology, barring any significant nerve damage, most incontinence sufferers can find relief.

Many of these women suffer in silence because they are too embarrassed to discuss these highly personal issues with their health care provider. Many women cope by limiting their daily activities and involvement in public events, which can have a profoundly negative impact on their confidence and self esteem. To further compound the problem, some physicians fail to respond appropriately to incontinence issues because it is frequently viewed as a “natural consequence of aging.”

Since joining the VCU faculty, Matthews has concentrated her research efforts on severe perineal lacerations sustained during vaginal childbirth, which can lead to incontinence, and on pelvic organ prolapse, POP.

In a 2005 study published in the American Journal of Obstetrics and Gynecology, Matthews and her team reported that women who have third- or fourth-degree perineal laceration repairs following the birth of their first baby have considerably different outcomes that can adversely impact quality of life and have implications on subsequent deliveries.

“This is an issue faced by many women who deliver vaginally and it is important that we educate women about the consequences of severe vaginal tears — especially mothers-to-be,” Matthews said.

“It is interesting how few women are educated about potential bowel-control problems after sustaining either a third- or fourth-degree tear,” she said. “It is our obligation as obstetricians to fully inform our patients.”

In this study, 56 women who sustained a third- or fourth-degree tear following their first vaginal delivery completed a questionnaire that assessed their pre-delivery bowel habits and bowel symptoms before being released from the hospital. Six to eight weeks later, patients completed another questionnaire to assess for any changes in bowel habits since delivery. This was followed by a pelvic examination and a special ultrasound of the anal canal that can determine if the muscles that were torn at delivery have healed.

Matthews’ team reported that bowel-related complications were more common following fourth-degree tear repair, compared with third-degree repair. Furthermore, women with fourth-degree tears were significantly more likely to have an increased rate of combined defects of the internal and external sphincters.

“Regardless of the initial degree of the tear, the status of the anal sphincter complex postpartum is very predictive of the likelihood of having bowel problems,” she said.

Following anal sphincter repair many woman experience incontinence of stool and fecal urgency. The overall reported rate of anal sphincter lacerations is approximately 6 percent to 20 percent, with higher rates documented following forceps or vacuum delivery, according to Matthews. Risk factors for anal sphincter damage include delivery with forceps or a vacuum, having your first baby or delivering a large baby. This research was supported in part by a grant from the A.D. Williams Foundation.

Bladder sling for urinary incontinence

Current treatment options for stress urinary incontinence come in the form of surgery, which at one time was considered invasive but has progressed to minimally invasive techniques.

The midurethral sling is one such form of relief. Under local and spinal anesthesia, Matthews performs a non-invasive surgical procedure to insert the sling. Through a small incision, a permanent, woven mesh — or ‘sling’ — is introduced next to the urethra and the bladder. The mesh is surgically placed on either side of the bladder and sits without any tension underneath the urethra so that when people cough or sneeze the urethra rotates down and is compressed against this stable hammock of support. The surgery can be performed as outpatient or on a 23-hour admit.

Within the next few months, Matthews may be launching a multicenter trial to determine whether a new kind of “mini-sling” can be safely introduced in an outpatient setting. Subjects will report on pain perception, overall satisfaction and efficacy of the new device.

Following surgery, patients can go back to work within a week. Approximately 85-90 percent of women with stress incontinence are dry or significantly improved. Other than surgery, women with stress urinary incontinence can perform kegel exercises, take medications, use an incontinence pessary or have peri-urethral bulking injections. Matthews said that none of these therapies is a successful as sling surgery.