PROGRAM IN REPRODUCTIVE AND ADULT ENDOCRINOLOGY
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, fibroids, infertility, and endocrine aspects of disease—both basic and clinical. The PRAE has earned national recognition as a leader in the field; in fact, 10 percent of the papers accepted for presentation at the American Society for Reproductive Medicine Annual Meeting came from the Program.
In the past year, the Section on Developmental Genomics, led by Wai-Yee Chan, used Serial Analysis of Gene Expression (SAGE) and microarrays to establish an expression database of mouse male germ cells and developing embryonic gonads. Analysis of the germ cell database revealed the prominent presence of antisense transcripts. Of particular interest is the existence of antiparallel transcription unit pairs; such unit pairs may interact through hybridization between a transcript and the pair’s antisense transcript, with the latter derived from the pseudogene embedded in the intron of the former. 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 “hotspots” with significant gene activities at any time of development. The chromosome 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 of mouse development is a study of the role of luteinizing hormone/choriogonadotropin receptor (hLHR) in human development and diseases. Observations 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.
The Unit on Pediatric Endocrinology and Tomoshige Kino investigate the glucocorticoid signaling system and the clinical implications of changes in tissue sensitivity to glucocorticoids and to serve as the world’s referral center for analyzing pathologic mutations of the glucocorticoid receptor (GR). This past year the unit continued to describe mutations in the glucocorticoid receptor (GR) gene that lead to glucocorticoid resistance. The unit also discovered that the brain-specific cyclin-dependent kinase 5 (CDK5), which is essential for brain development and has implications for the pathogenesis of Alzheimer’s disease, phoshorylates the GR at multiple serine residues and regulates its transcriptional activity in a target gene-specific fashion. Given that glucocorticoids are pivotal for brain function, these findings suggest that aberrant activation of CDK5 may exert its pathologic actions also by modulating glucocorticoid action. The unit further examined the biologic activity of chemical compounds 3-O-formyl-20R, 21-epoxyresibufogenin and 3-O-formyl-20S,21-epoxyresibufogenin, isolates from Chinese toad skin extract known as the 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, and/or action of IL-6 type cytokines play important pathologic roles. Members of the group also published a landmark review in Trends in Endocrinology and Metabolism on virus-mediated modulation of host endocrine signaling systems and their clinical implications, based primarily on their work on the involvement of HIV-1 proteins on nuclear receptor signaling systems.
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 autoantibodies and histologically confirmed autoimmune oophoritis, a mechanism of 46,XX spontaneous premature ovarian failure. Nelson’s group is also investigating the physiology of the normal ovarian aging process. Researchers have shown that, of the several markers of ovarian aging subjected to testing, age correlated most strongly with FSH-stimulated serum inhibin B levels. In work on the psychological response to the diagnosis of spontaneous premature ovarian failure, the group 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, published a landmark article in Endocrine Reviews on the hypothalamic pituitary adrenal axis (HPA) in pregnancy; during pregnancy, diagnosis of HPA disorders presents a challenge. The section completed a study comparing immunometric and radioimmunoassay measurement of ACTH for differential diagnosis of Cushing’s syndrome. The section continues to work on the diagnosis and management of patients with hypercortisolism, recently focusing on the diagnosis and management of ectopic ACTH-secreting tumors and their localization. The section also investigates 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. CD10 cell-surface metalloendopeptidase is present in normal endometrium, and staining of the protein is helpful in diagnosing endometriosis.
The Section on Medical Neuroendocrinology, under the direction of Karel Pacak, has made significant contributions in the neuroendocrine area, particularly with respect to pheochromocytoma. The section used micro CT for early diagnosis of ectopic pheochromocytoma tumor in the liver of the nude mouse, a technique that can be applied to humans and 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 such disease originates 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 gene mArd2, and demonstrated 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 susceptible risk factors for thrombophilia and age-related macular degeneration, providing a more accurate tool for risk calculation and disease prediction for these two complex disorders.
James Segars heads the Unit on Reproductive Endocrinology and Infertility. The laboratory addresses disparities in access to reproductive services and treatment. Collaborative work established a complex relationship between the BRX gene complex and fibroid generation, and the laboratory is expanding its work on several aspects of fibroids, including gene regulation and growth factors. The primary hypothesis posits that fibroid growth is in some way associated with attempts at healing and inflammation. With regard to fertility, the Walter Reed Army Medical Center’s Assisted Reproductive Technologies Program continues to provide material for clinical studies. In addition to continuing to capitalize on and encourage work already in progress, the Center plans to enlarge its consultative service; to increase the number of fellowships to three per year (already approved), thus making Walter Reed’s fellowship program the largest Reproductive Endocrinology and Infertility Fellowship Progam in the country; and to develop several protocols, including one on abnormal bleeding mechanisms and treatment. A major effort will focus on treating patients diagnosed with cancer who wish to preserve fertility through the use of various drug regimens. In addition, the oocyte physician program is almost entirely in place, involving investigators at the NIH and in Livingston, New Jersey.
