New Pilot Studies

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• Diets based exclusively on soy (vegetable) protein, rather than animal protein, may actually reduce calcium absorption to undesirable levels.

The work of Dr. Karl Insogna has shown that the amount of protein women eat profoundly affects how efficiently calcium is absorbed by the intestinal tract.  Specifically, at dietary protein intake levels just below the current recommended dietary allowance, we know that calcium is poorly absorbed.  Since many Americans have low-protein diets, problems with calcium being adequately absorbed may be more prevalent than is recognized in the adult population.  This is particularly important for postmenopausal women, in whom the risk for osteoporosis is greatest. This finding is confirmed by Dr. Insogna’s related research showing that in large, population-based studies, women who habitually consume low-protein diets have lower bone mass.  One source of protein that has recently gained popularity is soy.  In research funded by Women’s Health Research at Yale, Dr. Insogna’s laboratory has shown that diets based exclusively on soy (vegetable) protein, rather than animal protein, may actually reduce calcium absorption.  The basis for this is currently being studied, but this finding raises the question of how to use soy and other sources of protein in our diets.  Taken together, these findings indicate that the amount and type of protein in our diets has important long-term consequences for skeletal health, and this work may result in revised dietary guidelines on optimal protein and calcium intake for bone health. [CLOSE]

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• Preliminary results indicate that when black cohosh is used concurrently with traditional types of chemotherapy, it can either increase or decrease the effectiveness of the treatment, depending on the specific type of chemotherapy used.

Women with breast cancer are increasingly turning to alternative medicines, either to supplement their traditional cancer treatment or to treat conditions for which traditional medicines are not recommended (such as estrogen to treat menopausal symptoms). One herb often used to treat menopausal symptoms by women who have stopped taking hormone replacement therapy is black cohosh.  This herb is purchased over-the-counter and has been advertised as safe and effective for the treatment of menopausal symptoms.  Yet, such over-the-counter agents do not require the approval of the Food and Drug Administration and have not been the target of scientific inquiry. Dr. Sara Rockwell’s research, funded by Women’s Health Research at Yale, is designed to investigate the effect of black cohosh on breast cells. The preliminary results of this research indicate that when black cohosh is used alongside traditional types of chemotherapy, it can either increase or decrease the effectiveness of the treatment, depending on the specific type of chemotherapy used. Furthermore, it is also possible that black cohosh increases the levels of toxicity associated with traditional chemotherapy drugs. With the use of complementary and alternative medicines on the rise, it is critically important to determine whether these agents are safe.  Armed with the facts, patients can make informed decisions about their treatment.   [CLOSE]

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• One way in which estrogen seems to have a protective effect against degenerative changes in blood vessel walls is by inhibiting a protein that recruits damage to artery walls.

The earliest recognizable event in atherosclerosis is an increased influx of inflammatory cells, called macrophages, into the arterial wall. Recent data indicate that a specific protein, known as monocyte chemotactic protein-1 (MCP-1), may act to recruit macrophages to the artery wall. In a project funded by Women’s Health Research at Yale, Dr. Aydin Arici studied the impact of estrogen on MCP-1 using a mouse model. The results of this study suggest that one way in which estrogen seems to have a protective effect against degenerative changes in blood vessel walls is by inhibiting MCP-1. This finding provides unusual insights into the mechanisms of estrogen’s action. Better understanding of the selective molecular mechanisms of estrogen’s action may lead to the development of improved estrogenic substances which preferentially affect certain tissues, such as heart, rather than others, such as breast. These new agents may provide more targeted interventions for women and provide a major benefit to their health. [CLOSE]

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• 85% of fertile women display normal patterns of a particular marker of endometrial functioning (MAG). Among women with infertility, only 20% reveal normal patterns of MAG. Nearly 30% of women with infertility had none of this marker.
• Due to the direct correlation between successful embryo implantation and levels of MAG, a test of MAG expression can help guide the physician and patient toward the most effective infertility treatment.

During most attempts of assisted reproductive technology (ART), fewer than 10% of embryos successfully implant. Abnormalities in the process of implantation may underlie infertility in many women, and undermine the effectiveness of ART. Predictors of implantation potential are needed, both to better understand the causes of infertility in women and to improve the efficacy and reliability of embryo transfer. Despite almost two decades of ART, the precise molecular mediators of human implantation remain unknown. As a corollary to this problem, no molecular markers exist that adequately predict whether implantation will occur during any given assisted cycle. Previous research by Dr. Kliman identified an endometrial marker (MAG) that may change this, finding that MAG is either absent, or expressed at the wrong time in patients whose assisted attempts fail. Since the majority of endometrial samples studied thus far have been from patients seeking treatment for infertility, there was little information on the prevalence of MAG expression abnormalities in the general female population. In research funded by Women’s Health Research at Yale, Dr. Kliman was able to evaluate MAG expression in normal, reproductive age women compared to women with unexplained infertility to establish the incidence of this abnormality.  In this study, Dr. Kliman found that 85% of fertile women display normal patterns of MAG expression. Among women with infertility issues, only 20% revealed normal patterns. Nearly 30% of women with fertility problems had none of this marker. Due to the direct correlation between successful embryo implantation and levels of MAG, Dr. Kliman has determined that a test of MAG expression can help guide the physician and patient toward the most effective infertility treatment. The results of these studies should provide new information about the significance of MAG expression in clinical settings where high rates of normal implantation are desired, and thus inform the clinical practice of assisted reproductive technologies. [CLOSE]

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• Negative mood is strongly related to smoking behavior for both women and men.
• Women are more likely than men to smoke to cope with stress or negative mood.
• As mood worsens, smokers:
  • smoke more quickly
  • smoke more cigarettes
  • inhale the smoke more deeply
  • inhale for a longer duration
  • and inhale a larger volume of smoke over 30 minutes

In her research, funded by Women’s Health Research at Yale, Dr. Sherry McKee examined the impact of gender and mood on smoking behavior in a laboratory setting. In this study, daily smokers engaged in a task designed to increase negative or positive emotion, followed by a 30-minute smoking period. For both women and men, negative mood was strongly related to smoking behavior. Specifically, participants high in negative mood, compared to those with a more positive mood, started smoking more quickly, smoked more cigarettes, inhaled the smoke more deeply, inhaled for a longer duration, and inhaled a larger volume of smoke over the entire 30 minutes. Additionally, if negative mood was high and individuals believed that smoking would help them to feel better, they smoked more cigarettes, smoked more deeply, and inhaled a larger volume of smoke over the entire 30 minutes. The results of this project advance our understanding of how mood and specific ways of thinking influence smoking behavior. These findings suggest that when designing more effective ways to quit smoking, it is crucial to include methods for reducing negative emotion as well as for challenging beliefs that smoking is a good means to improve mood. [CLOSE]

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• One type of protein has been identified that may trigger Systemic Lupus Erythematosus (SLE), providing information that could be used in the prevention and treatment of this disease.

A major question in understanding SLE is how specific proteins in the body, called autoantigens, become targeted for attack by the immune system.  The goal of the work of Dr. Mark Mamula has been to identify the specific factors that may trigger this disease. In studies first supported by Women’s Health Research at Yale, Dr. Mamula’s research group has been able to identify one type of protein that may trigger SLE. Overall, these studies have addressed mechanisms important in understanding what starts and maintains diseases of the immune system.  A more thorough understanding of the earliest processes in such diseases is an important first step to identify potential targets for treatment of SLE. [CLOSE]

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• Women are significantly more depressed after a cardiovascular event compared to men, and participation in cardiac rehabilitation resulted in a significant improvement in levels of depressive symptoms.
• Guided imagery added to cardiac rehabilitation resulted in further decreases in depressive symptoms and a significant decrease in markers of arterial inflammation.

Half of all Americans with heart disease today are women, and this disease has claimed the lives of more women than men in every year since 1984. Recent studies have demonstrated that depression and stress may aid in the development of heart disease by contributing to inflammation of coronary arteries. Traditional cardiac rehabilitation programs are recommended as part of therapy after cardiac events in order to decrease the psychological effects of heart disease, control cardiac symptoms, decrease the risk of another heart attack and death, and prevent progression of the disease.  It has been shown that women respond less well to traditional rehabilitation. Funded by Women’s Health Research at Yale, Dr. Teresa Caulin-Glaser studied a complementary medicine technique known as guided imagery added to traditional cardiac rehabilitation for women who have had a heart attack, angioplasty or coronary bypass surgery. Guided imagery is a process of creating a mental image to help a patient achieve a state of relaxation. The study demonstrated that women are significantly more depressed after a cardiac event compared to men, and participation in cardiac rehabilitation resulted in a significant improvement in levels of depressive symptoms to a greater degree in women than men. The addition of guided imagery to cardiac rehabilitation was associated with a greater improvement in depressive symptoms compared to cardiac rehabilitation alone, especially in women. Finally, the addition of guided imagery to traditional cardiac rehabilitation was associated with a significant decrease in markers of inflammation affecting arteries. This research advances our understanding of the importance of assessing multiple risk factors for cardiac disease, including depression and inflammation, and demonstrates promise for novel techniques related to complementary medicine. [CLOSE]

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• Specific molecular markers in the tumors of women with breast cancer were related to BRCA1 and BRCA2 status. This relationship was even stronger in young women with a particular type of cancer (intraductal cancer) compared to women with later onset disease.
• A surprisingly high frequency of BRCA1 and BRCA2 mutations was found in Korean women. Yet, despite the high frequency of mutations found, the rate of breast cancer was much lower in Korean women, suggesting that another factor (genetic or environmental) may account for the onset of the disease in American women.

Breast cancer initially occurring in those at a young age (less than 42 years old) has unique biological characteristics compared to later onset disease. However, the genetic and molecular characteristics of early onset breast cancer that set it apart from later onset breast cancer have not been extensively examined. In an attempt to understand the genetic contribution to early onset disease, Dr. Haffty previously tested patients for the breast cancer susceptibility genes, BRCA1 and BRCA2, and found that these genes do incur increased risk for recurrence of cancer in the untreated breast. In a follow-up study funded by Women’s Health Research at Yale, Dr. Haffty and colleagues expanded on that work by analyzing the primary tumor specimens of patients with early stage, early onset breast cancer. These tissues were examined for several molecular markers commonly expressed in breast tumors and associated with the biological activity of the cancer cells. The study found that specific molecular markers in the tumors of women with breast cancer were related to BRCA1 and BRCA2 status. This relationship was even stronger in young women with a particular type of cancer (intraductal cancer) compared to older women. Additional research then found a surprisingly high frequency of BRCA1 and BRCA2 mutations in Korean women. Yet, despite the high frequency of mutations found, the rate of breast cancer was much lower in Korean women. Furthermore, family members of the women with mutations had a low frequency of breast and ovarian cancer. This suggests that another factor (genetic or environmental) may account for the onset of the disease in American populations. Dr. Haffty and his research laboratory continue along this avenue of translational clinical research, which remains relatively underexplored. This research is directed toward detection of breast cancer as well as understanding its mechanisms. [CLOSE]

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• The discovery of sex-specific effects of genes will help scientists better understand the development of alcoholism and will facilitate the development of treatment and prevention strategies for women and men.

Alcoholism among women is common, debilitating, and likely to be genetically influenced. Previous research suggests that genetic factors involved in the risk to develop alcoholism may be sex-specific, in that either women may have different genes than men that predispose them to alcoholism or the effect of the same genes may be different in women and men. Funded by a grant from Women’s Health Research at Yale, Dr. Jaakko Lappalainen is working to identify the female-specific genetic components that affect risk for alcoholism. Dr. Lappalainen has already ruled out one specific gene that does not appear to have an impact on alcoholism in women. Determining the sex-specific effects of genes will help scientists better understand the development of alcoholism and will facilitate the development of treatment and prevention strategies tailored to gender. Dr. Lappalainen’s results also will contribute to an increase in public awareness about the impact of biological factors on alcoholism. [CLOSE]

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• Even mild, uncontrollable stress can impair the functioning of the prefrontal cortex of the brain (an area involved in emotion, memory, and concentration) and this effect is more pronounced in females.
• These gender differences seem to be specifically related to the levels of estrogen circulating within the body, and may relate to an evolutionary connection between the role of estrogen and sensitivity to environmental threat.

Symptoms of depression and of posttraumatic stress disorder (PTSD) are twice as prevalent in women as in men. Dr. Amy Arnsten’s research, funded by Women’s Health Research at Yale, focuses on how the biology of the brain affects this gender difference. Exposure to uncontrollable stress is a major risk factor for depression, and exposure to a traumatic, life-threatening stressor can induce symptoms of PTSD. Dr. Arnsten’s laboratory has found that exposure to uncontrollable stress markedly impairs function in an important area of the brain, the prefrontal cortex (an area involved in emotion, memory, and concentration). Her studies in animals demonstrate that even mild, uncontrollable stress can markedly impair the functioning of the prefrontal cortex, and this effect is more pronounced in females. Furthermore, these gender differences seem to be specifically related to the levels of estrogen circulating within the body. It is interesting to speculate that a greater sensitivity to stress under conditions of high estrogen may have evolved to protect pregnant or fertile females, making them more cautious and thus enhancing their rate of survival. However, in human society, these same chemical actions may render women more vulnerable to the symptoms of depression and PTSD. These results should encourage women to seek treatment when depressive symptoms arise in response to life stressors. It is also hoped that understanding the neurobiological basis of these symptoms may facilitate a more compassionate, constructive attitude toward depressive and stress-related disorders. [CLOSE]

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• Estrogen may play a role in mood disorders, such as depression, by influencing a major mechanism that sustains brain cells, including those important for mood.

In research funded by Women’s Health Research at Yale, Dr. Ronald Duman has investigated the impact of estrogen on the expression of BDNF. His results demonstrate that estrogen influences the expression of BDNF, suggesting a route by which fluctuations of hormones could contribute to neurobiological dysfunction. Moreover, interactions between fluctuating hormones and stress could further compromise the functioning of neurons. These findings can be used to develop strategies for counteracting the effects of stress and hormone fluctuations on BDNF expression and neuronal functioning. Continued research and progress in this area will eventually lead to a more complete understanding of the cellular basis of the effects of hormones on mood. [CLOSE]

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• A laboratory test of ovarian cancer cell responsiveness to various therapeutic drugs predicted the clinical response of patients with ovarian cancer over 75% of the time.
• Such laboratory tests have the potential to increase the effectiveness of chemotherapy choices and reduce exposure to treatments that are unlikely to be useful while inducing unnecessary side effects.

Ovarian cancer remains a disease that is unlikely to be detected in its early stages. Consequently, scientists continue their commitment to developing the most effective treatments for ovarian cancer. Funded by Women’s Health Research at Yale, Drs. Barry Kacinski and Maryann Flick have worked to develop a measure of the sensitivity of ovarian cancer cells to therapeutic drugs. In this study, the researchers compared the response of specific tumor cells in the laboratory to the response of the patient with ovarian cancer in a clinical setting, utilizing two of the most widely used types of chemotherapy for ovarian cancer. Their results showed that the laboratory test correctly predicted the patient’s response to chemotherapy over three-quarters of the time. Practical tests to predict the likelihood of individual tumor responses to particular drugs are very much needed. Such tests would permit the choice of anti-cancer agents to which the patient’s tumors are most sensitive, and avoid treatment with drugs to which a tumor is already resistant, thus avoiding unnecessary drug side-effects while maximizing available treatments. [CLOSE]

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• Ductal lavage is a minimally invasive procedure that holds the promise of early detection of cell abnormalities indicating risk for breast cancer.
• Preliminary findings have identified genetic abnormalities in cells that may indicate an increased probability of a cell becoming cancerous.

Research by Dr. Bonnie King focuses on the development of a new approach for breast cancer screening that involves the analysis of cells regularly shed from the breast. This technique, called ductal lavage, is a new method of collecting breast duct cells to detect early changes associated with the development of breast cancer. Her previous work has shown that the method is safe, well tolerated, and able to detect early abnormalities in high-risk women. Building upon this initial research, Dr. King’s Women’s Health Research at Yale-funded investigation resulted in preliminary identification of genetic abnormalities that may indicate an increased probability of a cell becoming cancerous. The intraductal approach offers an exciting new dimension for early detection of breast cancer, risk assessment, and even therapeutic approaches for breast cancer. The clinical significance of ductal lavage findings awaits the validation of ongoing, long-term research. [CLOSE]

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• The interaction of genetics, brain chemistry, and sex hormones (such as estrogen) plays an important role in the sex differences seen both in depression and smoking behavior.

Women have a more difficult time quitting smoking than men and are also more likely to be depressed. The goal of Dr. Marina Picciotto’s research, funded by Women’s Health Research at Yale, is to begin to understand the relationship between these two health concerns for women. Using an animal model to investigate these issues, Dr. Picciotto and her laboratory found evidence that genetics play a role in whether female animals are more likely to show depressive-like behavior than male animals. In addition, they found that certain molecular structures in the brain that are responsive to nicotine are related to both depressive behavior and the pleasant effects of nicotine, suggesting that smoking may be used to decrease depressive symptoms. Interestingly, female, but not male, mice prefer to drink a nicotine solution rather than water, perhaps indicating that female mice are more sensitive to nicotine. Further, mice who have had their ovaries removed no longer prefer nicotine, suggesting that sex-specific hormones such as estrogen may be important in maintaining smoking behavior. Taken together, these findings suggest that nicotine-responsive molecular structures in the brain affect both smoking behavior and depressive symptoms. This work demonstrates that understanding the interaction of genetics, brain chemistry, and sex hormones will lay the foundation for developing new treatments that are more effective in helping women to stop smoking. [CLOSE]

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• Only 54% of women hospitalized with a heart attack presented with a chief complaint of chest pain, compared with 69% of men. Although women tended to present less often with a chief complaint of chest pain in all age groups, this sex difference was most marked in older patients.
• The second most common chief complaint was respiratory (breathing) problems, and younger women were twice as likely to present with respiratory symptoms as their chief complaint than were men of the same age.

Women who suffer a heart attack tend to have less typical symptoms and signs, and are less likely to receive recommended treatments compared with men. Despite their relative lack of traditional diagnostic indicators of heart attack, women have more severe clinical abnormalities and higher mortality than do men. Because of less typical presentations, women may delay longer in reaching the hospital, and health care providers may delay appropriate treatments - leading to a higher mortality in women. Less typical presentations may also lead to delayed identification of coronary disease in women, with women being diagnosed and treated at more advanced stages of the disease compared with men. In a study funded by Women’s Health Research at Yale, Dr. Vaccarino investigated the relationship between presentation characteristics, process of care, and outcome of acute coronary ischemia in women, using a large population-based cohort of female and male heart attack patients from the Worcester Heart Attack Study. The results of this study indicate that only 54% of women hospitalized with a heart attack presented with a chief complaint of chest pain, compared with 69% of men. Although women tended to present less often with a chief complaint of chest pain in all age groups, this sex difference was most marked in older patients. The second most common chief complaint was respiratory (breathing) problems, and younger women were twice as likely to present with respiratory symptoms as their chief complaint than were men of the same age. Overall, a large number of both women and men who were ultimately diagnosed as having a heart attack did not present with chest pain as their chief complaint. The clarification of gender differences in clinical presentation of acute coronary ischemia will help physicians recognize and treat heart disease in women more promptly, resulting in improved outcomes for women. [CLOSE]

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• Processes by which ovarian cancer cells spread to other organs have begun to be identified.
• Preliminary evidence has been found for the effectiveness of a gene therapy-type approach to reducing the invasiveness and spread of ovarian cancer.

As ovarian cancer is unlikely to be detected in its earliest stages, it usually presents after it has metastasized (spread) and led to widespread tumors throughout the abdominal cavity. Because of this, individuals diagnosed with ovarian cancer have only a 15% chance of surviving 10 years. Consequently, scientists must continue to develop effective treatments for this cancer. The work of Dr. Setsuko Chambers, funded by Women’s Health Research at Yale, has begun to identify molecular processes by which cancer cells spread to other organs. This research has found preliminary evidence for the effectiveness of one gene therapy-type approach to reducing the invasiveness and metastasis of ovarian cancer in an animal model. In gene therapy, a gene that is absent or defective is replaced by a healthy gene. The next step in this work is to determine if these results can be successfully translated from the laboratory to the medical care of women, with the goal of significantly advancing the treatment of ovarian cancer. [CLOSE]

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• A standardized health message does not generate the same response in every listener.
• Recommendations about health behaviors, such as mammography, are most effective in changing behavior when customized to an individual’s preferred way of gaining new information.

Breast cancer is the second leading cause of cancer death among American women. Although mammography is generally regarded as the most effective tool for detecting breast cancer early and preventing cancer death, many women do not obtain regular mam¬mograms. To motivate women to use routine mammography screening, more effective public health messages are needed. In experiments funded by Women’s Health Research at Yale, Dr. Peter Salovey and his research team examined the persuasiveness of health messages when they are matched to individuals’ information-processing styles. Re¬search findings clearly show that everyone does not respond in the same way to a given health message. For example, there are individual differences in the willingness to attribute the responsibility for maintaining good health to self or to health professionals (known as health locus of control). Overall, the results of Dr. Salovey’s research indi¬cate that recommendations about health behaviors, such as mammography, are most effective when cus¬tomized to an individual’s preferred way of gaining new information. His research demonstrated that women who received messages consistent with their health locus of control were more likely to obtain a mammogram 6 and 12 months later than women who received messages that were not consistent with their health locus of control. These findings have impor¬tant implications for the ways physicians, nurses, other health care professionals, and health-related websites provide health information. [CLOSE]

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• The study’s results indicated that 64% of the HIV-positive women studied were also HPV-positive. This suggests that, as a group, HIV-infected women are at increased risk of anal cancer.
• Clinical indicators have been identified to assist in the detection of women who are at high-risk of anal cancer, without having to use an anal pap smear.

Anal cancer in women has increased in recent years and is likely to continue to do so. However, cervical cancer has declined drastically as a result of pap smear screening programs. Since the mechanisms of cervical and anal cancer appear to be similar, a common prevention approach for the two types of cancer may be worthwhile. Human Papillomavirus (HPV) infection has been associated with both anal and cervical disease. Research designed to develop a cost effective method of anal cancer screening should be of particular benefit to Human Immunodeficiency Virus (HIV)-positive women who are at high-risk of HPV infection and cervical disease. Dr. Williams received funding from Women’s Health Research at Yale to determine the effectiveness of anal HPV testing and cellular screening in the identification of pre-cancerous anal lesions in HIV-infected women. The study’s results indicated that 64% of the HIV-positive women studied were also HPV-positive. This suggests that, as a group, HIV-infected women are at increased risk of anal cancer. The researchers also identified clinical indicators to assist in the detection of women who are at high-risk of anal cancer, without having to use an anal pap smear. [CLOSE]

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• An animal model of autoimmune factors related to Tourette’s Syndrome (TS) and Obsessive-Compulsive Disorder (OCD) was successfully developed. However, this model did not appear to account for the sex difference in TS and OCD prevalence seen in humans.

We propose to explore the development of these disorders and associated sex differences using a newly developed animal model. Funded by Women’s Health Research at Yale, Dr. Lombroso’s research focused on an autoimmune hypothesis (in which the body generates an anti-infection response against its own cells) as a possible cause for some cases of TS and OCD. Specifically, the research tested the hypothesis that exposure to certain bacterial and viral illnesses in childhood invoke an immune response that produces substances in the blood (i.e. antibodies) to fight the infection. However, the antibodies that are produced also recognize the body's brain proteins and compromise their normal activity (thus, they become known as autoantibodies. The results of this study indicated that certain TS and OCD patients did have higher autoantibodies than those in the control groups. ). Dr. Lombroso hypothesized that for patients with these autoantibodies, developing OCD or TS depended on the patient’s gender. Next, the researchers were able to show that placing small amounts of these autoantibodies into specific brain regions of rats produces repetitive movements, called stereotypies, that can be considered an animal model of tics. Because males typically have TS four times more frequently than females, Dr. Lombroso attempted to reproduce this sex difference in the animal model. However, after infusing autoantibodies into male rats and into female rats, no sex differences in the frequency or intensity of stereotypies were found. [CLOSE]

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• Burning Mouth Syndrome (BMS) is associated with severe taste damage, often to the part of the tongue that detects bitter tastes. When taste is damaged, it results in abnormal activity in a specific part of the brain producing oral pain sensations.
• BMS is more prevalent in “supertasters” (those born with an unusually large number of taste buds), and women are more likely than men to be supertasters. Taste damage in supertasters results in particularly intense BMS.
• Ability to taste bitter declines after menopause, and this loss of taste puts supertasting women at special risk for BMS.

Dr. Linda Bartoshuk suspected that BMS was a sensory phantom (that is, caused by abnormal activation of the part of the brain that recognizes oral pain). Funding from Women’s Health Research at Yale allowed her to confirm this hypothesis. Two new discoveries emerged from the research, showing that those with BMS had severe taste damage (most typically, they could not taste bitter on the tips of their tongues), and they were also supertasters (individuals born with unusually large numbers of taste buds). To understand why these findings are important, it is helpful to know a little bit about the sensory system involved in taste. The taste of food activates taste nerves. The taste nerves then carry the sensory information to the proper area of the brain. In addition to receiving taste input, this same area in the brain is responsible for blocking oral pain. When taste is damaged, this part of the brain no longer inhibits the oral pain. This results in abnormal activity in a specific part of the brain producing oral pain sensations. This type of damage in supertasters results in particularly intense BMS. As a result of this work, we now understand why postmenopausal women are at special risk for BMS. First, women are more likely than are men to be supertasters. Second, the ability to taste bitter functions as a poison detector. The intensity of bitter varies with the menstrual cycle, peaks in early pregnancy and diminishes after menopause. This pattern suggests that the ability to taste bitter might be protective during pregnancy. However, the loss of the ability to taste bitter at menopause puts supertasting women at special risk for BMS. Dr. Bartoshuk’s groundbreaking research on this underrecognized syndrome has led to specific recommendations for treatment, using a simple piece of candy containing a substance known as capsaicin. This substance, which is commonly found in cayenne pepper, acts by desensitizing the pain receptors in the mouth responsible for BMS. [CLOSE]

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• One type of protein has been identified that may trigger Systemic Lupus Erythematosus (SLE), providing information that could be used in the prevention and treatment of this disease.

Although the specific causes of the disease are unknown, SLE is the product of a complex interaction of white blood cells, proteins, and body tissues. In this disease, instead of being protective, the immune system actually attacks such tissues as heart, kidney, skin, and blood vessels. A major question in understanding SLE is how specific proteins in the body, called autoantigens, become targeted for attack by the immune system. The goal of the work of Dr. Mark Mamula has been to identify the specific factors that may trigger this disease. In studies first supported by Women’s Health Research at Yale, Dr. Mamula’s research group has been able to identify one type of protein that may trigger SLE. Overall, these studies have addressed mechanisms important in understanding what starts and maintains diseases of the immune system. A more thorough understanding of the earliest processes in such diseases is an important first step to identify potential targets for treatment of SLE. [CLOSE]

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• Women with mutations of BRCA1 or BRCA2 genes are significantly more likely to develop reoccurrence of breast cancer in either breast, following treatment for an initial occurrence, than are women without this genetic risk factor.

In this study, funded by Women’s Health Research at Yale, Dr. Haffty focused on the analysis of risk for reoccurrence as a function of whether or not women had a possible genetic predisposition to breast cancer. The results of this research indicate that women with mutations in BRCA1 or BRCA2 genes are significantly more likely to develop additional tumors in either breast following treatment for an initial occurrence of breast cancer than are women without this genetic risk factor. These findings also provided the impetus for expanding this work to African-American and Korean populations of women who had never previously been studied. In an attempt to further understand the characteristics of early onset breast cancer, Dr. Haffty also is funded to conduct research testing the molecular markers associated with early-stage, early onset breast cancer. These results will provide important information related to the prognosis for the disease, and prediction of response to standard treatments in women with breast cancer. [CLOSE]

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• The findings support a role for estrogen in the maintenance of body fluids by adjusting vascular functioning.
• The findings further indicate that high plasma progesterone levels reverse the protective effects of estrogen on plasma volume.

Estrogen and progesterone, in particular, may mediate disease effects through the regulation of body fluid balance and dynamics. Improper body fluid balance can lead to debilitating illnesses (including certain cardiovascular diseases), to surgical complications, and to problems with body temperature regulation. The Women’s Health Research at Yale funded research of Dr. Stachenfeld was designed to characterize the actions of estrogen and progesterone on the systems that regulate body fluid balance. Estrogen and progesterone have opposing effects on water regulation, and they usually increase concurrently in women of reproductive age, thereby making it difficult to study the individual actions of these hormones. In this investigation, the natural production of estrogen and progesterone in young women was prevented using a an agent that suppresses ovarian function. Natural estrogen, as well as combined estrogen and progesterone, were then added back to determine if estrogen and progesterone alter body fluid distribution. The findings support a role for estrogen in the maintenance of body fluids by adjusting vascular functioning. The findings further indicate that high plasma progesterone levels reverse the protective effects of estrogen on plasma volume. This study improves understanding of body fluid regulation, which may lead to the eventual prevention and/or treatment of chronic diseases that specifically affect women. The findings also improve our understanding of the influence of fluid dynamics on responses to temperature challenges, and facilitate in the development of new strategies to help women avoid heat exhaustion or heat stroke. Understanding the role of estrogen and progesterone on body fluid regulation may further result in strategies for decreasing surgical complications due to fluid imbalance. Thus, increased knowledge of the effects of these female sex hormones on fluid regulation adds significantly to the treatment of diseases involving body fluid regulation with particular relevance to women's health. [CLOSE]

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• Women’s violence almost always occurs in the context of male violence against them.
• When women respond to their partner’s abuse with violence, this often results in more severe violence against them.

Most research on the perpetration of intimate aggression has rightly focused on male violence, which is the primary cause of women's injury-related emergency room visits. However, the causes, correlates and outcomes of women's use of violence in intimate relationships are not well understood. There are a number of compelling reasons from the standpoint of women's health to focus on women's violent behavior, as well as their victimization. First, although women (particularly young women) respond to their partner's abuse with violence, this strategy appears to be a risk factor for increased and more severe violence against them by their male partners. Second, women's motives for aggression against intimate partners may differ from men's motives. Some evidence suggests that women's violence stems primarily from self-defense, fear, and retaliation for violence perpetrated against them. Third, women who use violence appear to have a disproportionately high incidence of childhood and adult trauma. Funded by Women’s Health Research at Yale, Dr. Swan conducted a study of women’s use of violence in intimate relationships. A principal finding of this study is that women’s violence almost always occurs in the context of male violence against them. Secondly, the types and frequencies of abuse women use differ from men. When compared to their male counterparts, women were more often victims of more serious types of abuse, including sexual coercion and injury, while women used equivalent levels of emotional abuse and more moderate levels of physical violence against their partners. Data from this study were used to develop and examine empirically a theory of the predictors and correlates of women’s violence. Future research is being designed to test and refine the theory and explore the impact of culture, race, and ethnicity on women’s use of violence. [CLOSE]

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• Women experience more difficult recovery from coronary artery bypass graft (CABG) surgery than men after leaving the hospital.
• Within the first two months after the surgery, women:
  • report more physical problems and side effects (such as infection) than men
  • report lower levels of physical functioning
  • report more depressive symptoms
  • are almost twice as likely as men to be readmitted to the hospital

In research funded by Women’s Health Research at Yale, Dr. Viola Vaccarino and her colleagues explored differences in recovery from CABG in both women and men. In this study of over 1,000 individuals receiving the CABG procedure, Dr. Vaccarino found that women experience more difficult recovery after leaving the hospital than do men. Within the first two months after the surgery, women reported more physical problems and side effects (such as infection) than men, lower levels of physical functioning, more depressive symptoms, and were almost twice as likely as men to be readmitted to the hospital. These results were found even after accounting for pre-existing conditions and risk factors, and preliminary findings at six month follow-up appear to confirm these results. The reasons for these significant sex differences must be investigated in future studies, so that additional interventions can be developed to improve the health status of women after CABG surgery. Continuing in this line of research, Dr. Vaccarino is currently studying differences in presenting symptoms in male and female heart attack patients. Her ongoing study is designed to improve the recognition and prompt treatment of heart disease in women. [CLOSE]

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• There was a significant interaction between gender and perceived social support on two measures of pain at 6 months post-surgery; women who had lower perceived social support reported higher pain than women with higher perceived support, whereas men reported similar levels of pain regardless of their social support.

Women are 4-5 times more likely to injure their knees severely during sports, tearing the anterior cruciate ligament (ACL) which provides stability to the knee. In research funded by Women’s Health Research at Yale, Drs. Ickovics and Galloway investigated gender differences in recovery trajectories following knee surgery, based on the rate and extent of rehabilitation throughout the six months after surgery. Specifically, they studied psychosocial factors proposed to influence recovery in women and men. Among ACL patients, men reported slightly higher knee function at 3 weeks and 6 months, although there were no gender differences on biomechanical function, or patients’ ratings of their pain. Among meniscectomy patients, men had higher knee function scores on one scale at baseline, but there were no gender differences on patient-rated knee function after surgery, or on physician-rated recovery at any measurement period. On patient-rated pain measures, there were also no consistent gender differences. However, there was a significant interaction between gender and perceived social support on two measures of pain at 6 months post-surgery; women who had lower perceived social support reported higher pain than women with higher perceived support, whereas men reported similar levels of pain regardless of their social support. This finding suggests that social support may play a role in women’s long-term recovery in terms of pain. [CLOSE]

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• A mechanism is being identified that can interfere with the functioning of ovarian cancer cells, thus potentially “weakening” the cells and making them more vulnerable to chemotherapy.

The Women’s Health Research at Yale-funded research of Dr. Dannies seeks to test a mechanism for making chemotherapy more effective. In a project employing innovative molecular techniques, Dr. Dannies has studied potential ways to interfere with the normal functioning of cells in order to “stress” the cells and, thus, make them more susceptible to toxic agents such as those used to treat cancer. One routine event in every cell is the folding of newly made, or synthesized, proteins into a special compartment in the cell called the secretory pathway. All cells need to make such proteins, and all cells have a secretory pathway through which the proteins are transported to where they belong. Cells have mechanisms to help proteins fold, and feedback systems to increase these “help mechanisms” if needed. When cells are forced continually to make proteins in the secretory pathway that cannot fold, the cells become “stressed.” Dr. Dannies was able to find a protein that cannot be folded properly or disposed of easily by the secretory pathway of ovarian cells. Future research will test a method believed to cause all ovarian cells to make this protein, using techniques developed for gene therapy. The next step is to test the degree to which producing this protein stresses the cells so that they are more susceptible to chemotherapy. This study has significant implications for a method of increasing the effectiveness of chemotherapy and improving outcomes for ovarian cancer patients. [CLOSE]

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• Women with depression during pregnancy have altered markers of melatonin (a hormone that among other functions affects mood) functioning that were corrected with successful light therapy treatment. This response is similar to that seen in individuals undergoing light treatment for seasonal depression.
• These findings suggest that bright light therapy has antidepressant effects in depressed pregnant women, regardless of the season.

For almost two decades, scientists have known that bright light therapy can be an effective treatment for winter seasonal depression. Various scientific and historical reasons led pregnant women with depression to be excluded from such studies. As a result, the value of a benign and successful physiological antidepressant treatment remains unknown in a population that might benefit from it especially. Supported by Women’s Health Research at Yale, Drs. Epperson and Oren conducted a study of the value of light therapy for depressed pregnant women. The women enrolled in the study were provided with one of two intensities of light therapy for 60-minute treatments each morning. Of the two intensities, one is known not to provide benefit for mood symptoms, while the other has been shown to be effective (placebo condition). Weekly evaluations of mood and energy were used to allow comparison of the efficacy of the two intensities. Results of this study showed that women with depression during pregnancy have altered markers of melatonin functioning that were corrected with successful light therapy treatment. This response is similar to that seen in individuals undergoing light treatment for seasonal depression. These findings suggest that bright light therapy has antidepressant effects in depressed pregnant women, regardless of the season. This study provides support for the use of light therapy as a safe, effective treatment of depression in pregnant women, without the use of medication. [CLOSE]

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• Female animals that have been "stressed" or have received drugs of abuse (such as cocaine, amphetamine or nicotine) are more sensitive to "reward" cues in controlling their behavior. These findings suggest that females may be more prone to relapse to drug use when provoked by stress or re-exposure to drugs than males because they are seeking the “rewarding" properties of drugs.
• Female rats show reduced impulsivity in tests of sustained and divided attention compared with male rats, effects that are important for normal cognitive performance. These data suggest that estrogen may protect some aspects of cognitive function.

New research is showing that women have increased sensitivity to several of the behavioral effects of cocaine and other stimulants, including nicotine. This sensitivity results in women becoming more rapidly dependent on such drugs after starting to use them. Despite these types of findings, limited research has focused on the behavioral and neurobiological processes that result in drug addiction for women. In prior work studying male rats, Dr. Jane Taylor found drug-induced changes in brain cellular activity that resulted in persistent alterations in sensitivity to drugs. These alterations in drug sensitivity were seen when testing the effects of different motivational processes to obtain drugs. In research funded by Women's Health Research at Yale, Dr. Taylor investigated how motivational processes in female animals are affected by stress and by psychomotor stimulants. She also examined sex differences in impulsiveness and cognition using animal models of attention. Dr. Taylor found that both "stressed" female rats and those having received drugs of abuse (such as cocaine, amphetamine or nicotine) are more sensitive to cues associated with "rewards" for behavior. These data are consistent with the idea that females may be more prone to relapse to drug use when provoked by stress or re-exposure to drugs than males because they are seeking the "rewarding" properties of drugs. Interestingly, female rats showed reduced impulsivity in tests of sustained and divided attention compared with male rats, effects that are important for normal cognitive performance. These findings are consistent with the high incidence of attention loss in disorders such as attention deficit/hyperactivity disorder (ADHD), which is more prevalent in males compared with females. The results also suggest that estrogen may protect aspects of cognitive function. These data have significant implications for novel gender-based pharmacological and behavioral treatment strategies for drug addiction as well as for hormonal treatment as part of therapy. [CLOSE]