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Program in Reproductive and Adult Endocrinology

Director: Alan DeCherney, MD

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The Program in Reproductive and Adult Endocrinology (PRAE) conducts biomedical research and training as well as clinical activities in the area of reproductive endocrinology and adult endocrinology. Physician-scientists from all Sections and Units of the Program admit patients to NIH's 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 as well as Reproductive Endocrinology and Infertility (REI), the former approved by the Accreditation Council for Graduate Medical Education (ACGME) and the latter by the American Board of Obstetrics and Gynecology. The Program takes three REI fellows (one in the military track) and two medical endocrine fellows per year. The medical endocrinology training program (The NIH Inter-Institute Endocrinology Fellowship Program) is a joint effort with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institute of Dental and Craniofacial Research (NIDCR). The PRAE collaborates closely with the 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., an MPH, Duke University Program in Clinical Research).

Lynnette Nieman leads the Section on Reproductive Endocrinology, 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; it was submitted to the EMA (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, and 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 studies explore aspects of glucocorticoid action and will continue. Nieman’s research has shifted away from the study of fibroids. 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 on Medical Neuroendocrinology, led by Karel Pacak, 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 for 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. To assist in its research and objectives, the Section also established a unique PHEO tumor tissue and blood bank. 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 evaluating new chemotherapeutic compounds that target identified proteins and pathways); (iii) facilitate new and improved collaborations and interdisciplinary studies and support a coordinated approach to basic and clinical research, which 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 to investigate molecules that interact with the gonadal steroid receptors in development of reproductive tissues (uterus, ovary, breast) or tumorigenesis. A second focus is the pathobiology of common and rare uterine leiomyomata (fibroids) and the underlying abnormalities in signal transduction, particularly relating to the estrogen receptor–interacting, A-kinase anchor protein AKAP13 and to extracellular matrix formation. In addition to its basic and translational studies, the Unit has forged collaborations 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 understanding the genetic underpinnings in rare cases of hereditary, early onset fibroids. Segars also initiated and co-directs the NICHD-sponsored leiomyoma tissue bank.

Segars also serves as the director of the Reproductive Endocrinology and Infertility Training Program and supervises Reproductive Endocrine Fellows on various clinical projects related to infertility, assisted reproduction, and clinical outcomes.

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 the National Heart, Lung, and Blood Institute (NHLBI) under John Tisdale and with NICHD under Alan DeCherney. Her work aims to characterize the effects of stem cell therapies on the reproductive tract, with the long-term goal of developing cellular therapy applications for gynecologic conditions. Currently, the only option for women suffering from idiopathic premature ovarian failure/primary ovarian insufficiency or from ovarian failure resulting from chemotherapy or radiation is donor eggs from younger women. Recently, several new stem cell advances have been made that could be used in future to treat women with premature ovarian aging. Until recently, it was thought that female ovarian germline stem cells did not exist. However, such cells have now been isolated in both a murine and human models, using magnetic beads and FACS with antibodies against the germ line marker Ddx4, cultured ex vivo with mitotic expansion, and transplanted in murine and human xenograft models. Adult germline stem cells were able to enter into meiosis after transplantation back into a donor ovary, where they gave rise to offspring in mice. The goal of this project is to translate the technical advances in stem cell research into ways to help women with reproductive disorders. However, significant differences in reproductive physiology exist between rodents and primates (e.g., menstrual cycles and hemachorial placentation), which make it essential to perform proof-of-concept studies in a non-human primate to determine the viability of the approach for future human therapy.

The NIH Inter-Institute Endocrinology Fellowship Program provides a comprehensive training experience that involves many of the NIH clinical branches working in endocrinology, as well as the Georgetown University Hospital, Washington Hospital Center, and Walter Reed Army Medical Center, all in the Washington area. The basic and clinical endocrine research facilities at the NIH are among the most extensive and highly regarded in the world. The fellowship is thus ideal for physicians who seek a broad education in both research and clinical endocrinology. Clinical training occurs largely in the first year. The remaining two years are spent primarily conducting laboratory or clinical research under the direction of a senior investigator in one of the several endocrinology branches of the NIH. During this research period, active clinical experience continues through a weekly continuity outpatient clinic, consult service, and participation in clinical conferences.

Fellows are responsible for five to ten patients at any one time on the inpatient service of the NIH. Under the supervision of the endocrine faculty, the trainee has total responsibility for all aspects of the patients’ care. Fellows make daily rounds, discuss patients with the attending physicians, and participate in management decisions related to both patient care and clinical investigation. Although all patients are admitted under peer-reviewed research protocols, there are many other aspects of diagnosis and patient care that fall completely under the discretion of the endocrine fellows. In addition, fellows on the endocrine service serve as consultants to the rest of the Clinical Center, where patients are not selected with regard to endocrine problems. Thus, the fellows gain experience with several common problems of endocrine disease that may occur in any general medical ward. Clinical research activities include programs in all the areas of endocrine and metabolic diseases. Study design, outcome measures, statistical analysis, and ethical and regulatory issues are stressed.

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