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Program in Reproductive and Adult Endocrinology

Director: Alan DeCherney, MD

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The Program on Reproductive and Adult Endocrinology (PRAE) performs biomedical research and training and clinical activities in the area of reproductive endocrinology and adult endocrinology. Physician-scientists from all Sections and Units of the Program admit patients to the Clinical Research Center for research-directed, approved clinical protocols and see patients in the outpatient setting for protocol evaluation, follow-up, and consultations. The PRAE trains fellows in Adult Endocrinology and Reproductive Endocrinology and Infertility (REI), the former being approved by the Accreditation Council for Graduate Medical Education (ACGME) and the latter by the American Board of Obstetrics and Gynecology.

The goal is to train the clinician-scientists of the future. The PRAE takes three REI fellows (one of whom is in the military track) and two medical endocrine fellows per year. The medical endocrinology training program is a joint effort with NIDDK. The Program collaborates closely with pediatric endocrine fellows, and all three fellowships include rotations on the adult endocrine unit and joint conferences. Elective time has been added to allow the fellows the opportunity to obtain advanced degrees (e.g., MPH, Duke University Program in Clinical Research).

The Section on Implantation and Oocyte Physiology is led by Alan DeCherney. Abnormalities in embryonic development can prevent the establishment of pregnancy or contribute to obstetrical disorders associated with aberrant placentation. Through basic and translational research, the mission of this Section is to identify critical cellular and molecular events required for successful implantation and to understand their relationships to pathologies of early pregnancy. The Section's objective is to understand the biology of the developing blastocyst, which requires differentiation of its outer epithelium, the trophectoderm, into invasive trophoblast cells and maintenance of a cohort of pluripotent embryonic stem cells. Signals received by the embryo from the female reproductive tract guide the embryonic developmental program and coordinate it with the maternal component. Although the preimplantation embryo can develop outside the reproductive tract and is capable of gestating to term, the consequences of omitting maternal-embryonic interactions during the preimplantation period are poorly understood. Efforts focus on investigating signaling molecules generated in the uterine environment that regulate trophoblast differentiation and survival and their role in pathological disorders associated with placental insufficiency.

Lynnette Nieman leads the Section on Reproductive Medicine, which currently conducts a clinical and basic research program on cortisol physiology and pathophysiology. Previous studies with the antiprogestin CDB-2914 formed the basis for FDA approval of the agent as a morning-after pill in 2010 and will be submitted to the EMEA (European Medicines Agency) in 2012 for approval for the treatment of symptomatic leiomyoma. Nieman's research interest in both adrenal and reproductive steroids dates to her initial work, in 1983, with the antiprogestin and antiglucocorticoid agent mifepristone. Since that time, her group has helped to develop diagnostic tests and their interpretation for the differential diagnosis of Cushing's syndrome, including salivary and midnight cortisol, 8 mg dexamethasone suppression, the CRH stimulation test, the dexamethasone-CRH test, inferior petrosal sinus sampling, high dose Octreoscan and FDG-PET imaging. The work continues with current studies on F-DOPA PET and the use of mifepristone for the treatment of ectopic ACTH secretion. A database of Cushing's syndrome patients has been constructed. Current and future studies explore aspects of glucocorticoid action. Nieman's research has shifted away from fibroid study. It is planned that this Section will change its name to Section on Clinical and Translational Endocrinology to more accurately reflect current research emphasis.

The Section includes the Unit on Endocrinology Training, headed by Smita Abraham, who is Associate Director of the Inter-Institute Endocrinology Training Program (IETP), a joint NICHD-NIDDK program.

The Section on Medical Neuroendocrinology is led by Karel Pacak. The Section was established in 2001 to develop novel approaches for the diagnosis, localization and treatment of pheochromocytoma (PHEO) and to search for new molecular and genetic markers to the etiology of this tumor. Initial studies focused on the development of novel methods and criteria to diagnose and localize pheochromocytoma. Current studies focus mainly on how to further characterize the tumors, using functional imaging approaches, identifying new molecular and genetic mechanisms of tumorigenesis, and introducing new treatment options for malignant pheochromocytoma. Currently, the Section has the world's largest population of patients with malignant and succinate dehydrogenase subunit B-related pheochromocytomas. The Section also established a unique PHEO tumor tissue and blood bank to assist in its research and objectives. Finally, the Section promotes interactive dialogue between patients and healthcare professionals by introducing and organizing a series of conferences in collaboration with the Pheochromocytoma Research Support Organization (PRESSOR). The Section's current goal is to introduce new algorithms for diagnosis and localization of PHEO) in order to: (i) explain the molecular basis for different clinical presentations and establish the pathways of tumorigenesis (focusing on genotype-phenotype correlations in various pheochromocytomas, using gene expression and proteomic profiling); (ii) search for new molecular and genetic markers for diagnosis and treatment of malignant pheochromocytoma (using microarray and proteomic approaches and evaluate new chemotherapeutic compounds targeting identified proteins and pathways); (iii) facilitate new and improved collaborations and inter-disciplinary studies and support a coordinated approach to basic and clinical research that should lead to an improved understanding of the biology of pheochromocytoma and more rapid advances in treatment for patients with malignant tumors.

The Unit on Reproductive Endocrinology and Infertility is led by James Segars. A major focus of the Unit is the importance of molecules that interact with the gonadal steroid receptors in development of reproductive tissues (uterus, ovary, breast) or tumorigenesis. A second focus of the laboratory is the pathobiology of common and rare uterine leiomyomata (fibroids) and the underlying abnormalities in signal transduction, particularly relating to AKAP13 and extracellular matrix formation. In addition to its basic and translational studies, the Unit has forged collaboration with NCI and NHGRI to study rare fibroid syndromes using SNP arrays followed by the next-generation sequencing technique of whole-exome sequencing, as an approach to develop an understanding of the genetic underpinnings in rare cases of hereditary, early onset fibroids.

Segars also serves as the Director, Reproductive Endocrinology and Infertility Training Program and supervises Reproductive Endocrine Fellows on various clinical projects related to infertility, assisted reproduction and clinical outcomes. Segars also initiated and, with Paul Driggers, co-directs the NICHD-sponsored leiomyoma tissue bank.

The Unit on Reproductive Regenerative Medicine is led by Erin Foran Wolff. Wolff is a 2010 PRAE REI Fellowship graduate and was selected by a formally constituted NICHD Assistant Clinical Investigator Search Committee in a competitive process. For her independent translational research, Wolff is working with National Institute of Heart, Lung and Blood (NHLBI) under John Tisdale and with NICHD under Alan DeCherney. The scope of her work includes characterization of stem cell therapies on the reproductive tract, with the long-term goal of developing cellular therapy applications for gynecologic conditions.

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