Obstetrics and Gynecology

REPRODUCTIVE CANCER UNIT

Cramer Laboratory
Howley Laboratory
Mutter Laboratory

REPRODUCTIVE AND CLINICAL EPIDEMIOLOGY UNIT

REPRODUCTIVE DEVELOPMENTAL BIOLOGY UNIT

REPRODUCTIVE GENETICS UNIT

OVARIAN BIOLOGY UNIT

UROGYNECOLOGY UNIT

ACADEMIC CAREER ADVISORS

RESPONSIBLE CONDUCT OF RESEARCH

REPRODUCTIVE CANCER UNIT
Unit Chief: Daniel Cramer, M.D.,
Department of Obstetrics, Gynecology and Reproductive Biology
Brigham and Women's Hospital,

Cramer Laboratory

Dr. Cramer is a Professor of Obstetrics, Gynecology, and Reproductive Biology at Brigham and Women’s Hospital, Harvard Medical School. Trained in both Obstetrics and Gynecology and Epidemiology, Dr. Cramer has a long portfolio of past and current NIH grants related to the epidemiology of ovarian cancer, early menopause, and infertility including predictors of the outcome of in vitro fertilization. The study of risk factors for ovarian cancer has, in particular, been a career pursuit. Currently, Dr. Cramer leads grants related to the epidemiology and early detection of ovarian cancer and has recently been awarded an Ovarian Cancer SPORE (Specialized Program of Research Excellence) grant. Dr. Cramer has mentored several doctoral students in the Harvard School of Public Health’s Epidemiology Branch providing data for their thesis topics. He would welcome WRHR candidates who have an interest in the clinical epidemiology of gynecologic cancers or infertility.

Research in the Howley laboratory is focused on the molecular biology of papillomaviruses and the role of these viruses in carcinogenesis in the uterine cervix. There is compelling evidence associating several specific types of the human papillomaviruses (HPVs) with human cervical cancer. These “high risk” HPV types such as HPV16 and HPV18 encode two oncoproteins, E6 and E7, which target the important cellular growth regulatory proteins p53 and pRb, respectively. Dr. Howley has previously shown that E6 promotes the ubiquitylation and degradation of p53, and he and his laboratory are now interested in the general question of how proteins are recognized within the cell by the ubiquitin proteolytic machinery. The E6-promoted ubiquitylation of p53 is mediated by a cellular protein called the E6 Associated Protein (E6AP) that binds to E6 and participates directly in its ubiquitylation. He is interested in how E6AP is regulated and the identification of additional cellular proteins that E6AP targets in cells, either in the presence or absence of the viral E6 protein. He studies both the bovine papillomavirus (BPV), which has served as the prototype for studies of the molecular biology of the papillomaviruses, as well as the HPVs that have been associated directly with human cancer. One area of research in the laboratory has focused on the E1 and E2 regulatory genes encoded by the papillomaviruses. E1 and E2 together are required for the initiation of viral DNA replication and E2 has additional roles controlling viral transcription. Structure/function studies of the E1 and E2 regulatory proteins are being pursued. Proteomic studies are also being conducted to determine cellular interacting proteins key for viral host cell interactions. The laboratory has had a particular interest in other functions of HPV E6 proteins. In addition to promoting the ubiquitylation of p53, E6 functions in cellular transformation and pathogenesis through its ability to interact with specific cellular proteins. He is also studying additional mechanisms by which E6 may perturb normal cell functions and has identified the focal adhesion protein paxillin and the interferon response factor IRF3 as targets of E6.

Mutter Laboratory

Michels Laboratory

Dr. Michels’ research focuses on Women’s Health Epidemiology, with an emphasis on in utero and early life events and their association with the woman’s risk of chronic diseases later in life. Dr. Michels also has an interest in the role of diet in women’s health. Evidence is accumulating that perinatal factors are associated with chronic disease suggesting a life course approach to disease. Female cancers may take decades to develop and have their origin much earlier in life than previously appreciated. Birth weight and diet during early life may be related to several hormonally related cancers. Dr. Michels’ research group is trying to identify mechanisms underlying such observed associations. The role of diet in women’s health is not well understood. Methods in nutritional epidemiology need to be developed further as assessment methods can be improved. Dr. Michels’ research tries to overcome the limitations of currently used analytic methods by accounting for the interrelatedness of foods and nutrients and the complexities of diet composition and dietary patterns.

Hankinson Laboratory

Dr. Susan Hankinson is a member of the Channing Laboratory whose research group follows two large cohorts of women, the Nurses’ Health Study I (started in 1976 among 121,700 women) and the Nurses’ Health Study II (started in 1989 among 116,000 women). Dr. Hankinson’s research has focused on relationships between reproductive events and lifestyle factors, such as exogenous hormone use and dietary intake, and subsequent risk of uterine and ovarian cancer. In a landmark paper she reported that tubal sterilization decreased the risk for ovarian cancer. She is also actively researching the effect of endogenous hormones and growth factors on the risk for female reproductive tract cancers that has been facilitated by the introduction of biologic sampling from members of the Nurses’ Health Cohorts. In 1989, blood samples were collected from over 32,000 women in the NHSI. Currently, both blood and urine samples (timed according to their menstrual cycle) are being collected from about 30,000 women in the NHSII. Methodological studies demonstrated that a single blood sample reflects long-term hormone levels. Using these archived blood samples, Dr. Hankinson and her research group are prospectively evaluating relationships between steroid and protein hormone levels and risk of ovarian and uterine cancer in both post- and premenopausal women. Findings reported in collaboration with Dr. Barbieri have demonstrated that in healthy menopausal women, baseline serum concentrations of estradiol, estrone, estrone sulfate, dehydroepiandrosterone sulfate and prolactin are predictive of the risk of developing breast cancer. In the next series of studies, the relationship between basal hormone levels and uterine and ovarian cancer will be studied. Over the next several years, these two large prospective studies should add substantially to our understanding of how endogenous hormone levels influence the risk of reproductive tract cancer. Dr. Hankinson would be an ideal Research Mentor for those Scholars interested in epidemiologic studies that can address the relationship between reproductive hormones and women’s reproductive tract cancers.

Hunter Laboratory

Dr. David Hunter’s research program has focused on the etiology of leiomyomata, endometriosis and reproductive tract cancer in women. He is a member of the BWH Channing Laboratory, which maintains the Nurses’ Health Study, a long-running cohort of 121,700 U.S. women, and is project director for the Nurses’ Health Study II, a newer cohort of 116,000 women. The Nurses’ Health Study II cohort is ideal for examining relationships between environmental and genetic factors and reproductive problems including endometriosis and uterine leiomyomata. Working in collaboration with Drs. Barbieri and Marshall, the Hunter group has investigated the relationship between age, race, body mass index and reproductive history and the risk of uterine leiomyomata. He is co-chair of the NCI Breast & Prostate Cancer Cohort Consortium, a large collaboration project examining low penetrance genes and risk of these two cancers. Dr. Hunter has also collaborated with investigators in Tanzania to understand the relationship of nutritional status to progression of HIV disease and perinatal transmission. Dr. Hunter would be an ideal Research Mentor for those Scholars interested in the epidemiology of endometriosis and uterine leiomyomata and for those interested in applying genetic techniques to discover heritable causes of disease in a large cohort.

Lieberman Laboratory

Dr. Lieberman directs a multidisciplinary research program investigating a variety of areas related to pregnancy outcome, with a primary focus on term labor and birth. She has extensive experience in conducting large clinical trials and analysis of large data sets. She performs investigations in a variety of areas of obstetrics including method of delivery, fever in labor and vaginal birth after cesarean delivery. Much of her research focuses on the effects of labor management practices, particularly epidural analgesia, on outcomes for mother and infants. Dr. Lieberman was Principal Investigator of a NIH-funded study investigating whether epidural analgesia used for pain relief during labor is associated with an increase in abnormal fetal position at delivery. She is currently Principal Investigator of a federally funded randomized trial of 1000 women which brings together a multidisciplinary team of basic and clinical researchers to investigate the etiology, physiologic consequences and clinical correlates for mother and infant of epidural related fever. Dr. Lieberman has served as a thesis advisor, and on the thesis committees, for a number of doctoral students at the HSPH and has mentored over 30 students, residents, fellows and junior faculty conducting research projects.

Maas Laboratory

The establishment of a receptive uterine environment is critical for embryonic survival and implantation. While the molecular mechanism for uterine receptivity remains largely unknown, targeted mutagenesis in the mouse has provided important clues to the maternal regulators of this process. Dr. Maas’ laboratory has engineered mice that lack the function of Hoxa-10, a member of the Abdominal B (Abd B) class of Hox genes, and found that both male and female Hoxa-10 mutants are infertile. Like other Abd Hox genes, Hoxa-10 is expressed during embryonic patterning of the male and female reproductive tracts, and Hoxa-10 mutants exhibit malformations of the vas and epididymis in males and of the uterotubal junction in females. However, Hoxa-10 is also expressed in the adult uterus during implantation, suggesting that either reproductive tract malformations or a maternal requirement during implantation, or both, could underlie the female infertility defect. The laboratory has undertaken experiments to distinguish these potential mechanisms. The results show that Hoxa-10 mutant females exhibit impaired decidualization and an impaired vascular permeability response, and that the bulk of the infertility derives from a peri-implantation requirement for Hoxa-10 function. These results and others begin to localize the implantation requirement for Hoxa-10 function to one or more steps subsequent to the attachment reaction.

To place Hoxa-10 further into a molecular hierarchy regulating implantation, the lab has begun to examine potential regulators of Hoxa-10 expression. Recent work indicates that ovarian steroids are major regulators of Hox gene expression in the uterus during implantation. Taking advantage of the progesterone-inducibility of Hoxa-10 expression in the uterine stroma, gene expression profiling experiments are being used to identify downstream genes that Hoxa-10 regulates. These experiments reveal that Hoxa-10 is an important regulator of two critical events in implantation: stromal cell proliferation and local immunosuppression. For example, at the time of implantation, Hoxa-10 deficiency leads to a severe local immunological disturbance characterized by a polyclonal proliferation of T cells that occurs in place of the normal progesterone-mediated immunosuppression in the peri-implantation uterus. Further work is underway to elucidate Hoxa-10 function more fully in uterine implantation.

Crowley Laboratory

Quade Laboratory

The first major focus of the Quade laboratory is the pathobiology of mesenchymal neoplasms arising in the female genital tract. These tumors range from extremely common leiomyomata to rare, yet often fatal leiomyosarcomas and unusual, quasi-malignant proliferations. Our goal is to identify the molecular factors that cause these tumors and determine their malignant potential. Previously, we have shown that disseminated peritoneal leiomyomatosis, a clinically benign condition in which hundreds of fibroid-like tumorlets stud the peritoneum and omentum, is in fact a clonal metastatic process. In addition, we have studied intravenous leiomyomatosis and vulvar aggressive angiomyxoma, quasi-malignant conditions manifesting vascular and local invasion, and discovered that both proliferations are associated with t(12;14) and aberrant expression of HMGA2. HMGA2, a non-histone chromatin protein, also is rearranged in a number of benign mesenchymal neoplasms including uterine leiomyomata. The molecular factors accounting for the biological differences between leiomyomatosis or aggressive angiomyxoma and typical leiomyomata remain an area of interest. In other studies, we have sought to identify molecular changes that distinguish benign and malignant uterine smooth muscle tumors. First, we have shown that loss of heterozygosity (LOH) for chromosome 10, particularly the q arm, is very frequent in leiomyosarcomas, but not in leiomyomata. Second, we have developed several immunohistochemical markers (h-caldesmon and CD-10) as useful tools in the differential diagnosis of endometrial stromal neoplasms and cellular smooth muscle neoplasms. Third, transcriptional profiling has defined a small number of genes that segregate myometrium and typical leiomyomata from uterine leiomyosarcoma, and interestingly, atypical leiomyomata. Fourth and most recently, we are characterizing a cytogenetic subgroup of leiomyomata (and possibly some leiomyosarcomas) defined by the presence of t(10;17)(q22;q23) in on-going studies. The 10q22 breakpoint falls within MORF (MYST4), a histone acetyltransferase, and appears to be similar to rearrangements found in acute myelomonocytic leukemias.

The second major focus of the laboratory is the identification of genes important in human development. The Quade laboratory is part of a multi-disciplinary, multi-laboratory program project known as the Developmental Genome Anatomy Project. Balanced de novo chromosomal rearrangements are associated with congenital anomalies in some individuals. Our hypothesis is that these rearrangements result in the disruption or dysregulation of genes required for proper development. Phenotypes of DGAP cases that would be of potential interest to WRHR Scholars include uterine anomalies (e.g., bifid uterus), hypogonadism, and ovarian cysts.

Morton Laboratory

The Morton Laboratory has a major focus on understanding the biology of uterine leiomyomata, the most common pelvic tumors in women and a major cause of reproductive morbidity for women. The most common reason for hysterectomy is to treat uterine leiomyomata. Uterine leiomyomata may also contribute to infertility and pregnancy complications. Dr. Morton’s hypothesis is that a number of genes are involved in the pathogenesis of uterine leiomyomata. Mutations in these critical genes result in the transformation of a stable myocyte into a precursor cell capable of clonal expansion. A molecular cytogenetic approach is being used to identify genes involved in the pathogenesis and pathobiology of leiomyomata. During the past few years her group identified two genes dysregulated in uterine fibroids, HMGA2 and HMGA1, members of the family of high mobility group proteins. An effort is underway focusing on identifying the genetic sequence involved in the most common rearrangement in fibroids, a deletion of a segment of chromosome 7. To address a genetic liability to developing fibroids, a genome-wide scan has been initiated. Currently, questionnaires dealing with family history and blood specimens are being collected from families with a high prevalence of these tumors in female relatives. A web site has been established for patient recruitment and for other information about the Center for Uterine Fibroids at BWH (www.fibroids.net). Microarray analysis of uterine leiomyomata has been performed to determine a tumor signature that distinguishes benign uterine leiomyomata from leiomyosarcoma and studies are now underway to assess the signatures of different cytogenetic subgroups.

Kaiser Laboratory

The Kaiser laboratory has as its major focus understanding the molecular mechanisms by which pulsatile gonadotropin-releasing hormone (GnRH) specifically and differentially regulates the expression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) genes. The processes of reproduction are critically dependent on the precise episodic and periodic timing of the release of these hormones, which are in turn absolutely required for gametogenesis and gonadal steroidogenesis. The hypothalamic neuropeptide, GnRH, is released in a pulsatile fashion and transported to the anterior pituitary, where it binds to specific, high affinity receptors (GnRHR) on gonadotropes. The frequency and amplitude of pulsatile GnRH release varies temporally and developmentally, and this variation is critical for normal reproductive maturation and function. Varying patterns of pulsatile GnRH differentially regulate LH and FSH biosynthesis and secretion. This raises the question: how does a gonadotrope respond to varying frequencies of pulsatile GnRH with differential LH and FSH production? The laboratory is using four approaches to address this question. First, critical cis-acting elements in the LH and FSH genes that mediate GnRH responses, and the cognate trans-acting factors that bind to these elements, have been identified. Interestingly, these elements and factors are distinct among the gonadotropin genes. Studies are underway to determine the mechanisms by which these factors act and interact to mediate responses to pulsatile GnRH. Second, a perifusion system has been established that can be used to delineate the intracellular signal transduction pathways by which pulsatile GnRH acts to regulate gonadotropin gene expression. Third, because GnRHR concentration, a critical determinant of gonadotrope responsiveness, varies in response to different frequencies of pulsatile GnRH, studies are underway to understand the mechanisms of regulation of GnRHR gene expression itself by GnRH. Finally, another goal of the laboratory is to identify genetic mutations occurring in patients with defects in neuroendocrine control of reproduction. In particular, the effects of newly identified mutations in the GnRHR in patients with hypogonadotropic hypogonadism on signal transduction and on gonadotropin subunit gene expression will be studied, providing unique structure-activity information on GnRH action and GnRHR function, and potential insights into pathways of GnRH regulation of FSH and LH biosynthesis and secretion. It is expected that these studies will provide new insights into the mechanisms of the regulation of gonadotropins by GnRH, which may in turn provide a better understanding of reproductive development and lead to improved management of disorders of reproductive function.

Karumanchi Laboratory

The Karumanchi laboratory has a focus on understanding the role of angiogenesis and endothelial function in health and in disease. The current focus is to understand the pathogenesis of preeclampsia, a disorder characterized by abnormal placental angiogenesis and systemic endothelial dysfunction. The laboratory has isolated several novel angiogenesis related gene products released by the placenta into the blood stream, which are markedly elevated in patients with PE. They are currently characterizing these gene products and will test them in vitro and in vivo to see if they mimic the preeclamptic phenotype, namely proteinuria, hypertension and endothelial dysfunction. They have created an animal model for preeclampsia, which will be used to test the effects of compounds that affect angiogenesis. They are also in the process of characterizing new biomarkers in pregnant patients for use in the early diagnosis of preeclampsia and intra-uterine growth retardation.

Sukhatme Laboratory

The laboratory’s research efforts are both pre-clinical and translational. Most of the projects are in vascular biology aimed at understanding the molecular, cellular, and network mechanisms that govern small and large vessel formation during development and relating these findings to human diseases characterized by abnormal vessel formation or function or an altered systemic angiogenic state. The major focus is on tumor angiogenesis as well as a more recent foray into tumor-stromal interactions. Regarding the latter, they are trying to understand the role of coagulation in setting up an extracellular matrix that favors angiogenesis as well as tumor growth/invasion and strategies to combat this. Areas of clinical studies include anti-angiogenic therapy and angiogenesis monitoring for cancer, therapies to prevent vascular access stenosis in patients on dialysis, and on characterization of the anti-angiogenic state in preeclampsia (in a collaboration with S. A. Karumanchi).

Wilkins-Haug Laboratory

Subtle variations in gene sequence, known as polymorphisms, occur commonly and typically do not result in clinical disease. However, when such gene alterations exist in combination with one another or with other risk factors, disease-producing changes may result. Genetic polymorphisms that are recognized as risk factors in triggering abnormal clot formation are known as the thrombophilia alleles. In women, these thrombophilia polymorphims are implicated in adverse pregnancy outcomes such as preeclampsia, fetal growth restriction and abruption. However, the thrombophilia alleles such as Factor V Leiden, prothrombin-20110A and MTHFR are relatively common and most women with these gene changes do not experience adverse pregnancy outcomes. Additional risk factors are likely present among those women who experience pregnancy complications. While dietary, exposures and other potential covariables have been explored, the role of the corresponding fetal thrombophilia genotype is unknown. As the placenta represents a site of fetal gene transcription early in gestation, contribution of fetal genotype to the overall risk is potentially significant. Unanswered is the question - Is the risk of preeclampsia associated with clotting protein polymorphisms due to the mother’s allele, the fetal allele or a combination of both?

Dr. Wilkins-Haug's investigation of four thrombophilic genes in a population of women with preeclampsia defined by strict criteria (American College of Obstetrics and Gynecology) did not reveal frequencies that were significantly different from ethnically matched controls. Of note, however, the distribution of MTHFR 677 in the infant population deviated significantly from the expected transmission equilibrium of 50% from a MTHFR carrier mother. MTHFR 1298 showed a similar skewed distribution. This suggests that when ascertained through a diagnosis of preeclampsia, there exist a significant disequilibrium in MTHFR gene transmission such that the presence of these thrombophilic alleles simultaneously in both mother and fetus may result in aberrancy in the homocysteine pathway early in placental development. These findings support focusing additional research on maternal/fetal genotyping of other enzymes of this pathway, the potential of folate as an intervention and further characterization of genetic changes underlying uteroplacental insufficiency.

OVARIAN BIOLOGY UNIT
Unit Chief: Jonathan Tilly, Ph.D.
Department of Obstetrics, Gynecology and Reproductive Biology
Massachusetts General Hospital        

Tilly Laboratory

Dr. Tilly currently directs the research program of the Vincent Ob/Gyn Service at MGH, which includes basic, translational and clinical research, and the training of junior faculty, fellows and students in the design, execution and analysis of biomedical research experiments. His primary goal is to improve women’s reproductive health and overcome infertility through application of research discoveries using appropriate animal models and human tissues. Three examples of his approach to current problems in reproduction and women’s health are as follows. Dr. Tilly, and members of his laboratory, used genetic manipulation and inhibitor-based approaches in female mice and documented that premature ovarian failure and infertility resulting from conventional anti-cancer therapies (radiation or chemical treatment) occur as a result of inappropriate activation of a latent program of cell death existing in oocytes. They have taken this series of investigations one step closer to translational research by validating a small molecule that, when administered to mice in vivo, is capable of completely protecting ovaries from anti-cancer therapy. Based on these findings, they employed a xenograft model in which human ovarian fragments are placed in immunodeficient mice to confirm, in vivo, the efficacy of this small molecule in protecting human oocytes from anti-cancer therapy-induced death. This work is now in pre-clinical trials with non-human primates. In a second example, they have identified a single gene that when silenced by gene targeting in mice prolongs ovarian lifespan into very advanced chronological age, thereby eliminating the ‘mouse equivalent’ of menopause. In addition to providing the first proof-of-concept that normal aging of the ovaries – the principal event driving menopause – can be prevented, the generation of this animal model allows investigation, for the first time, of the impact of sustained ovarian function on the aging female body. Lastly, Dr. Tilly recently overturned one of the most basic doctrines in his field by demonstrating the existence of female germline stem cells that support new oocyte and follicle production in juvenile and adult mouse ovaries. These experiments open a number of new and exciting avenues based on therapeutic manipulation or transplantation of female germline stem cells to overcome infertility and possibly delay the timing of natural ovarian failure.

Rueda Laboratory

Cytokines, once thought to be ancillary factors to the functional aspects of ovarian function are proving to be active players. One of Dr. Rueda’s research areas is focused on determining the role of cytokines in ovarian function with emphasis on follicle and luteal development and their demise. Dr. Rueda is testing the significance of cytokine stimulated sphingomyelin hydrolysis in ovarian endothelial and steroidogenic cells. Increased sphingomyelin hydrolysis is believed to result in the production of the pro-apoptotic second messenger, ceramide. He postulates that elevated levels of ceramide inhibit both basal and gonadotropin-stimulated steroid production in the steroidogenic cells, and induce death of endothelial and steroidogenic cells. Understanding of the mechanisms that regulate cytokine-induced lipid signaling is crucial for developing therapies to combat infertility resulting from ovarian failure.

In collaboration with Dr. Lawrence Zukerberg (MGH Department of Pathology), Dr. Rueda has identified a protein that is lost with high frequency during the early stages of malignancy in the human endometrium. This protein, termed Cables, is a negative regulator of the cell cycle via its ability to enhance the inhibitory phosphorylation of the Cdk2 protein (a key modulator of the G1-S phase transition in mitosis). Consequently, loss of Cables function would theoretically result in uncontrolled cellular proliferation as a first step towards cancer. Studies have been completed showing that the expression of Cables is increased by progestin treatment and decreased by estrogen treatment in human endometrial epithelial cells. In addition, the cables mutant mouse shows evidence of atypical hyperplasia. More importantly, there is an increased incidence of endometrial cancer in the cables mutant mice subjected to chronic estrogen. These results are in agreement with the results of pathology specimen screening in which a consistent loss of Cables in all cancer biopsies and, most importantly, intermittent loss of the protein in those biopsies with pre-cancerous atypical hyperplasia was observed. The research focus has now expanded to include a parallel analysis of Cables expression in ovarian cancer. Serous adenocarcinoma and endometrioid carcinoma account for 42% and 15%, respectively, of all ovarian cancers in humans (57% combined). In both of these cancers, loss of heterozygosity (LOH) of 18q has been detected with high frequency. Given that the cables gene locus maps to chromosome 18q11-12, these data collectively suggest that loss of cables expression accompanying LOH of 18q plays an important role in ovarian cancer.

Endometriosis is a polygenic disease with complex multifactorial etiologies affecting reproductive-aged women. Although this disorder is commonly treated in clinical practice, the mechanisms by which ectopic endometrium is disseminated, established in the peritoneum and proliferates, is not completely understood. There are a number of different factors that have been implicated in either the genesis or the propagation of endometriosis. They include, but are not limited to, prostaglandins, cytokines, growth factors, chemokines, cell adhesion molecules and steroid hormones. It is, however, difficult to investigate the functional role of these factors without adequate in vivo model systems. Dr. Rueda currently is developing mouse models that have been manipulated to ‘mimic’ the human disease in order that he may study the effect of specific factors on the growth of ectopic endometrium. Using mutant mouse strains that are devoid or over-express one or more of the factors described above will help to delineate their cause and effect relationships with the pathogenesis of the disease. Using this strategy it is expected that his team will gain a better understanding of the underlying mechanisms of endometriosis. This information will also serve to develop more effective alternative treatment modalities.

Usheva-Simidjiyska Laboratory

A major direction in Dr. Usheva-Simidjiyska’s laboratory is to establish the molecular mechanisms that operate in the aging process of biological systems. She currently investigates changes at the level of ovarian gene expression profiles, gene expression regulation changes at the level of proteins and protein modifications. Dr. Usheva-Simidiyska’s laboratory is searching for signaling and transcriptional pathways that underlie the human aging-related infertility. She uses mouse ovaries and human granulosa cell model systems to approach it. Recent data from her laboratory suggests that structural changes in the nuclear chromatin organization due to metal-catalyzed protein oxidation and acetylation may play a significant role in the reproductive ovarian function by regulating the expression level of enzymes that are directly involved in the estrogen metabolism. Her hypothesis is that the local estrogen biosynthesis and the estrogen transformation may present a physiologic mechanism to regulate ovarian aging.

In collaboration with the National Laboratory at Los Alamos, Dr. Usheva-Simidjiyska’s laboratory investigates the dynamics associated with the formation of transcription initiation complex (TIC) using various time-resolved optical techniques. She is planning to apply this knowledge in studying fundamental processes in cellular and ovarian function at the atomic level.

UROGYNECOLOGY UNIT
Unit Chief: Francine Grodstein, Sc.D.
Department of Medicine
Brigham and Women's Hospital

Grodstein Laboratory

Dr. Grodstein’s research focuses on understanding determinants of healthy aging in women. A key aspect of this research is investigating the epidemiology of urinary incontinence. In addition to the medical, social and public health consequences of incontinence, the financial burden is substantial; estimated annual direct costs of incontinence in the United States are 16.3 billion dollars. Approximately 35% of women aged 65 years and older report urinary incontinence, and relatively few effective treatment options exist (especially for urge incontinence). Nonetheless, little research has been devoted to identifying ways to prevent incontinence or delay its onset. Dr. Grodstein leads a large epidemiologic study of risk factors for incontinence among 121,000 subjects of the Nurses’ Health Study – the largest ongoing epidemiologic study of incontinence. In initial research, important findings indicated that use of postmenopausal hormone therapy – often considered a beneficial treatment for incontinence – increased women’s risk of developing incontinence, results that have been confirmed in other studies. Future work includes examining the effect of type 2 diabetes on development of incontinence, as well as obesity, physical activity and various dietary factors. In addition, the availability of biologic specimens from subjects will allow exploration of genetic factors that may predict incontinence. Moreover, research is underway to determine health and lifestyle factors that predict progression of existing incontinence from mild to more severe leaking. Thus, there is a wealth of opportunities available for trainees to address a critical issue in women’s health.

Jolesz Laboratory

Current research in magnetic resonance focuses on both diagnosis and image guided therapy. A major focus of the Jolesz Laboratory is to use advanced MRI protocols to produce functional and dynamic images of pelvic floor muscles, bones and connective tissues in humans. Using adaptive spatial encoding methods for efficient sub-second dynamic MRI acquisition, the female pelvic floor can be functionally imaged. This research will help to explore the pathogenesis of pelvic floor disorders, plan surgical therapy and evaluate the effectiveness of both surgery and medical therapy for women with incontinence. Magnetic resonance imaging is also being applied to pelvic imaging that includes fetal imaging and assessment of fetal status using MR spectrospcopy. Magnetic resonance imaging also has particular advantages for guiding, monitoring and controlling therapeutic interventions. The MRI Division is investigating MR's unparalleled potential to not only monitor but also control interventional or minimally invasive surgical and gynecological procedures. Current investigations involve thermal therapies including the MRI-guided focused ultrasound treatment of uterine fibroids.

The Division of MRI embraces several distinct laboratories, of which Dr. Jolesz is also chair: the Surgical Planning Laboratory, the Therapeutic Ultrasound Laboratory, the Hyperpolarized Noble Gas Laboratory, and the Center for Adaptive Imaging.

Key research initiatives within the Division of Magnetic Resonance Imaging include:

• To refine the acquisition of real-time 3-D imaging of patients during surgery and minimally invasive interventions. SPL research is focused around developing post-processing methods for digital medical imaging data and to use these methods for real-life applications. There is substantial work within SPL to study the integrity of the female pelvic floor and its relationship to incontinence.
• To develop the clinical application of non-invasive ultrasound surgery including continued research into fibroid treatment and potentially the treatment of cervical cancer.
• To develop near-optimal adaptive spatial encoding methods for efficient sub-second dynamic MRI acquisition. Applications include interventional MRI and imaging of the pelvic floor.

ACADEMIC CAREER ADVISORS

A core goal of the BWH WRHR Program is to ensure that the Scholars have symmetrical mentoring, both from their primary Research Mentor and from an academic career mentor. The Academic Career Advisors are experienced members of the faculty, that have senior leadership positions in the academic Departments that can help guide the career development of the Scholars.

Robert L. Barbieri, M.D.
Chair, Department of Obstetrics, Gynecology and Reproductive Biology
Kate Macy Ladd Professor of Obstetrics, Gynecology and Reproductive Biology
Brigham and Women’s Hospital and Harvard Medical School

In the past, Dr. Barbieri’s laboratory focused on the role of hyperinsulinemia in the pathogenesis of the polycystic ovary syndrome. His current research is focused on the epidemiological and biochemical correlates of endometriosis and uterine leiomyomata. Dr. Barbieri served on the Reproductive Biology Study Section for five years (1991-1996) and was the Section Chairperson for three years (1993-1996). This experience will help him guide the Scholars as they prepare proposals for independent research funding.

Ross S. Berkowitz, M.D.
Department of Obstetrics, Gynecology and Reproductive Biology
Director of Gynecology and Co-Director of Women’s Cancers Program
William H. Baker Professor of Gynecology
Brigham and Women’s Hospital, Dana Farber Cancer Institute and Harvard Medical School

The current research interests of Dr. Ross Berkowitz concern the pathogenesis and treatment of ovarian cancer and gestational trophoblastic tumors and his research has resulted in more than 300 original reports and reviews. Dr. Berkowitz serves as the Director of the Gynecologic Cancer Program of the Dana Farber Harvard Cancer Center. His research in ovarian cancer primarily concerns the early pathogenetic events leading to borderline and invasive ovarian cancer and the identification of new biomarkers that may be useful for the early detection of ovarian cancer. Dr. Berkowitz’s research in gestational trophoblastic disease has concerned identifying risk factors for the disease and advancing understanding of the immunobiology of gestational trophoblastic diseases. His research is also focused on the development of improved therapy in gestational trophoblastic tumors and in advancing knowledge related to the subsequent pregnancy experience and quality of life of patients treated for gestational trophoblastic diseases.

Mark D. Hornstein, M.D.
Associate Professor of Obstetrics, Gynecology and Reproductive Biology
Director, Division of Reproductive Endocrinology
Brigham and Women’s Hospital and Harvard Medical School

A major focus of Dr. Hornstein’s research has been the medical treatment of endometriosis. In the late 1980’s, the gonadotropin releasing hormone agonists (GnRH) were approved by the FDA for the medical treatment of endometriosis. Their use, however, was limited to a six-month treatment period due to side effects, most notably bone loss. In a series of multi-center prospective studies, Dr. Hornstein’s laboratory was able to demonstrate: 1) the efficacy of short courses of therapy, thereby reducing side effects, 2) short retreatment courses are efficacious and safe, 3) post-operative GnRH-a use prolongs the treatment free interval in endometriosis-associated pelvic pain patients, and 4) hormonal add-back can largely eliminate side effects of GnRH-a therapy with a loss of efficacy for up to 12 months. On the basis of this last finding, the FDA approved an add-back regimen by 12 months of treatment. Currently, working with Dr. David Guzick of the University of Rochester, Dr. Hornstein is implementing a NIH RO1-sponsored prospective study comparing GnRH-a plus add-back treatment vs. continuous oral contraceptives in the treatment of endometriosis-associated pelvic pain.

Paula Johnson, M.D., M.P.H.
Chief, Division of Women’s Health
Executive Director, Mary Horrigan Connors Center for Women’s Health and Gender Biology
Assistant Professor of Medicine
Brigham and Women’s Hospital and Harvard Medical School

Dr. Johnson is a clinical epidemiologist and health services researcher whose focus has been to understand the relationship between clinical factors, gender, race and disparities in access to cardiology care and outcomes. Her research has also addressed assessing the quality of care in different models of primary care for minority women. Dr. Johnson has just completed a large study assessing the underutilization of cardiology interventions for women and minorities that also assesses patients’ preferences for treatment. Dr. Johnson has conducted her research in the Divisions of General Internal Medicine Cardiology, and Women’s Health at Brigham and Women’s Hospital. The Division of Women’s Health is able to provide a solid foundation for training.

Neeraj Kohli, M.D., M.B.A.
Director, Division of Urogynecology
Brigham and Women’s Hospital and Harvard Medical School

The Division of Urogynecology specializes in the diagnosis, treatment, and research of clinical conditions including urinary incontinence, overactive bladder syndrome, pelvic prolapse, and urogenital fistulas. Currently, the Division is involved in various clinical studies examining efficacy of minimally invasive surgical techniques for treatment of stress incontinence and pelvic prolapse. The Division has completed participation in the multi-center national trial examining the safety and efficacy of the MONARC transobturator sling procedure for treatment of stress urinary incontinence. It is currently enrolled in the multi-center international trial examining the safety and efficacy of the TVT-Obturator inside-out sling procedure that is expected to be completed by December 2004. With regard to prolapse, the Division is doing a retrospective analysis of its experience using synthetic polypropylene mesh in the treatment of advanced pelvic prolapse and has completed a case series review of both vaginal and abdominal reconstructive pelvic surgery with uterine preservation. With expansion of the Division, further basic science research regarding anatomy and pathophysiology of urinary incontinence and pelvic prolapse will be initiated. The Division is also active in integrating residents and fellows in clinical/basic science research under faculty supervision/mentorship.

Isaac Schiff, M.D.
Chief, Vincent Memorial Obstetrics and Gynecology Service
Joe Vincent Meigs Professor of Gynecology
Massachusetts General Hospital and Harvard Medical School

Dr. Schiff serves as the Editor-in-Chief of the journal, Menopause, and is Past President of the North American Menopause Society. He is Chairman of the ACOG Task Force on Hormone Therapy. He will serve as an Academic Career Advisor to scholars especially interested in reproductive aging. Dr. Schiff mentored these trainees when he was Chief of Reproductive Endocrinology at Brigham and Women’s Hospital in Boston.

Louise Wilkins-Haug, M.D.
Medical Director, Center for Fetal Medicine and Prenatal Genetics
Director, Division of Maternal-Fetal Medicine and Reproductive Genetics
Assistant Professor of Obstetrics, Gynecology and Reproductive Biology
Brigham and Women’s Hospital and Harvard Medical School

Dr. Wilkins-Haug will serve as both a Research Mentor and an Academic Career Advisor. Her research focus and trainees are described above in the Reproductive Genetics Unit.

Walter Willett, M.D.
Chair, Department of Nutrition
Professor of Nutrition
Harvard School of Public Health and Harvard Medical School

Dr. Walter Willett’s research program has dealt primarily with lifestyle and nutritional risk factors for chronic illness and women’s reproductive tract diseases. He has been a principal investigator on numerous studies using the two Nurses’ Health Study cohorts. His studies have addressed diverse and important topics including: alcohol use in relation to reproductive morbidity, postmenopausal hormone use in relation to reproductive cancers, and oral contraceptive use in relation to ovarian cancer. These topics are but a few of the associations investigated in more than 700 original reports by Dr. Willett addressing women’s reproductive health issues. Whenever an important issue in woman’s health is debated, data from the Nurses’ Health cohort are likely to be considered crucial and Dr. Willett’s name is likely to be associated with a key paper. Dr. Willett will be an ideal Mentor for those wishing to pursue a topic in nutritional epidemiology as it relates to women’s reproductive health.

Ruth Tuomala, M.D.
Department of Obstetrics, Gynecology and Reproductive Biology
Assistant Professor of Medicine
Brigham and Women’s Hospital and Harvard Medical School

Dr. Tuomala’s NIH-funded research provides opportunities for career development in epidemiologic studies and clinical drug trials concerning perinatal HIV disease as well as basic research studies concerning the virology and immunology of the lower genital tract in HIV-infected women. Dr. Tuomala’s areas of concentration within these funded research projects are: 1) the efficacy and safety of antiretroviral therapy during pregnancy, including the development of genotypic viral resistance, and 2) the relationship between vertical transmission of HIV and both the viral burden in the lower genital tract and the maternal lower genital tract immune response. Her other research projects involve studying the microbiological ecology and immunological response of the genital tract and how these relate to adverse pregnancy outcomes, and clinical perinatal issues related to infectious diseases.