Program in Reproductive and Adult Endocrinology
Alan DeCherney, MD, Program Director
The Program in Reproductive and Adult Endocrinology (PRAE) can point to a broad, comprehensive, and exceptional list of publications and activities in the areas of endometriosis, endocrine aspects of disease, both basic and clinical, fibroids, and infertility. The Program has earned recognition as a national leader in the field; in fact, 10 percent of the papers accepted for presentation at a recent annual meeting of the American Society for Reproductive Medicine came from the PRAE.
In the past year, the Section on Developmental Genomics, led by Wai-Yee Chan, established an expression database of mouse male germ cells and developing embryonic gonads through the use of Serial Analysis of Gene Expression (SAGE) and microarrays; the database revealed the prominent presence of antisense transcripts. Of particular interest is the existence of anti-parallel transcription unit pairs. Mapping the transcriptome of murine male embryonic gonads has allowed the creation of a chromosome heatmap of gonad development that permits researchers to highlight chromosomal “hot spots” with significant gene activities at any time of development; the heatmap will be useful for identifying the importance of different regions at specific time points during the development process and for determining the potential consequences of chromosome duplication or deletion. Related to these studies is a study of the role of luteinizing hormone/choriogonadotropin receptor (hLHR/hCG) in human development and diseases. Studies in cell models uncovered a novel role of hCG in neuronal development. Expression profiling revealed distinct genes and hence physiological changes triggered by two mutations of the same amino acid in hLHR.
Lawrence Nelson’s Unit on Gynecologic Endocrinology focuses on the pathophysiology and clinical management of spontaneous premature ovarian failure. The Unit demonstrated a highly significant association between circulating adrenal cortex auto-antibodies and histologically confirmed autoimmune oophoritis, which is a mechanism of 46,XX spontaneous premature ovarian failure. Nelson’s Unit is also investigating the physiology of the normal ovarian aging process, showing that, of several markers of ovarian aging, age correlated most strongly with follicle-stimulating hormone–stimulated serum inhibin B levels. Investigating the psychological response to the diagnosis of spontaneous premature ovarian failure, the Unit found that women with the condition perceive a need for clinicians to spend more time with them after making the diagnosis and to provide more information about the disorder.
The Section on Reproductive Medicine, headed by Lynnette Nieman, works on the hypothalamic pituitary adrenal axis in pregnancy, which presents a challenge for detecting disease and assessing the relative merits of immunometric and radioimmunoassay measurement of ACTH for differential diagnosis of Cushing’s syndrome. The Section continues its work on the diagnosis and management of patients with hypercortisolism, recently focusing on ectopic ACTH-secreting tumors and their localization. The Section continues to focus on endometrial physiology and endometriosis pathologies. It has published studies on the endometrium, describing the localization of lesions in women with endometriosis and characterizing the estrogen alpha receptor and use of raloxifene as an adjunctive treatment for endometriosis. The Section found that staining of CD10, a cell-surface metalloendopeptidase present in normal endometrium, is helpful in diagnosing endometriosis.
The Section on Medical Neuroendocrinology, under the direction of Karel Pacak, continues to focus on neuroendocrine disorders, particularly pheochromocytoma. The Section used micro computed tomography for early diagnosis of ectopic pheochromocytoma tumor in the liver of the nude mouse, a technique that may be applied to the human model and that would be an excellent way to diagnose early small metastases. In addition, members of the Section noted that mutations of the SDHB gene are associated with one-half of all malignancies originating from extra-adrenal paragangliomas. The high frequency of SDHB germline mutations among patients with malignant disease, particularly when originating from adrenal paraganglioma, may justify a high priority for SDHB germline-mutation testing in such patients.
The Section on Clinical Genomics, led by Owen Rennert, applies information gained from biochemical and genomic studies to clinical investigations. Using the database generated by the Section on Developmental Genomics, members of the Section on Clinical Genomics cloned several genes, including the novel mArd2, which demonstrates testis specificity and elevated expression in pachytene spermatocytes. Subsequent studies showed that Ard2 has acetyltransferase activity and may be responsible for compensating for the loss of X-linked transacetylation activity during meiosis and post-meiotic differentiation in germ cells. The Section also applied genomic approaches to the study of human diseases, designing two hybridization-based high-throughput methods for screening risk factors for thrombophilia and age-related macular degeneration. The methods will provide a more accurate tool for risk calculation and disease prediction for these two complex disorders.
James Segars and the Unit on Reproductive Endocrinology and Infertility addressed disparities in access to reproductive services and treatment. Collaborative work established a complex relationship between the BRX gene complex and fibroid generation, and the Unit is expanding its work on several aspects of fibroids, including gene regulation and growth factors. With regard to fertility, the Walter Reed Army Medical Center’s Assisted Reproductive Technologies Program continues to provide material for clinical studies. The Oocyte Physician Program, involving investigators at the NIH and the laboratory of Jacques Cohen in Livingston, New Jersey, looked at the effect of leiomyomas on early pregnancy, anti-Müllerin hormone pre- and post-myomectomy, and ovarian reserves in patients with fibroids. A new area of investigation has been the assessment and preservation of ovarian function in women and girls undergoing cancer treatment.
The Section on Pediatric Endocrinology continues to investigate the glucocorticoid signaling system and the clinical implications of changes in tissue sensitivity to glucocorticoids. It also serves as the world’s referral center for analyzing pathologic mutations of the glucocorticoid receptor (GR). This past year, the Section continued to describe mutations in glucocorticoid-resistant patients and to elucidate the molecular mechanisms of target-tissue glucocorticoid resistance. The Section also discovered that the brain-specific cyclin-dependent kinase 5 (CDK5) that is essential for brain development has implications for the pathogenesis of Alzheimer’s disease. It phoshorylates the GR at several serine residues and regulates its transcriptional activity in a target gene–specific fashion. The Section continued to examine the biologic activity of 3-O-formyl-20R,21-epoxyresibufogenin and 3-O-formyl-20S,21-epoxyresibufogenin, known isolates from the Chinese toad skin extract drug Ch’an Su, and discovered that these compounds act as inhibitors of IL-6–type cytokine action by attenuating the function of the common receptor subunit gp130. The results suggest that this class of compounds may be employed in the treatment of disorders in which excessive circulation/production/action of IL-6 type–cytokines play important pathologic roles.