PEDIATRIC AND REPRODUCTIVE ENDOCRINOLOGY BRANCH
George P. Chrousos, MD, Chief

The Section on Pediatric Endocrinology, led by George Chrousos elucidated the cellular pathophysiology of two new probands with familial/sporadic glucocorticoid resistance, describing three novel mutations of the glucocorticoid receptor and abnormalities in nuclear translocation and interactions with p160 coactivators. Members of the section demonstrated both inadequate cortisol secretion and pro-inflammatory cytokine-induced, NF-kappaB-mediated glucocorticoid resistance in patients with acute respiratory distress syndrome/systemic inflammation. They also demonstrated that FLASH, a plasma membrane-associated protein that mediates the proapoptotic effects of tumor necrosis factor alpha and Fas Ligand, is involved in inflammation-associated glucocorticoid resistance. They described two HIV-1 small accessory proteins, Vpr and Tat, as viral glucocorticoid receptor coactivators, proteins that were shown to participate in a similar coactivator complex in the HIV-1 LTR promoter. They demonstrated Vpr-mediated glucocorticoid hypersensitivity in several different systems, including interleukin-12 suppression, and discovered a dominant-negative Vpr mutant that can eliminate the coactivator activity of Vpr. The section established that a single oral dose of antalarmin inhibits stress behaviors in rhesus monkeys. Investigators found that, in rats, antalarmin ameliorates adjuvant-induced arthritis, blocks ulcer formation in stressed animals, and, by inhibiting aseptic inflammation and expression of Fas-ligand by the invasive cytotrophoblast, blocks blastocyst implantation. Studies on CAH established that an antiandrogen and an aromatase inhibitor control bone age and growth and allow smaller doses of glucocorticoids in children with severe classic CAH, that the disease is associated with severe adrenomedullary dysfunction, which correlates with the degree of the enzymatic defect and the molecular defect, that the epinephrine deficiency of CAH is associated with an inability of patients to increase their circulating glucose levels during exercise, that CAH is associated with insulin resistance and increases in plasma leptin level, and that children with CAH have structural changes in the brain, with significantly diminished amygdala size.
 

Under Lynette Nieman, the Section on Reproductive Medicine demonstrated marked comorbidity of endometriosis, autoimmune disorders, and bromyalgia. Nieman also established that midnight plasma cortisol or salivary cortisol is an excellent diagnostic test to distinguish Cushing's syndrome from pseudocushing states and demonstrated the utility of SPGR MRI for the identification of corticotrope tumors and of etomidate and octreotide for the treatment of Cushing's syndrome.

Led by Karel Pacak, the Unit on Clinical Neuroendocrinology found that plasma-free metanephrine levels are the best biochemical test for the diagnosis of pheochromocytoma, either alone or in combination with the clonidine suppression test. The unit also developed pediatric reference ranges for plasma-free metanephrines and validated their use for the diagnosis of childhood pheochomocytoma. Investigators developed the 6-[18F]-fluorodopamine PET scan for the diagnostic localization and follow-up of pheochromocytoma and the novel use of radiofrequency ablation in the treatment of pheochromocytoma.
 

The Unit on Reproductive Endocrinology and Infertility investigated a variety of clinical reproductive disorders. Studies that were an integral component of the Reproductive Endocrinology and Infertility Training Program, directed by James Segars, led to identification of the genes that contribute to uterine leiomyoma tumorigenesis as well as demonstration of the major role of Brx in the estrogen receptor and protein kinase signaling systems.