PEDIATRIC
AND REPRODUCTIVE ENDOCRINOLOGY BRANCH
|
George P. Chrousos, MD, Chief The
Pediatric and Reproductive Endocrinology Branch (PREB) had a long list of
published research achievements in the areas of glucocorticoid action,
interactions between the HPA axis and immune and inflammatory reactions, and
preclinical studies with the CRH receptor type 1 antagonist antalarmin,
congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency,
hypercortisolism, endometriosis, anovulation, infertility, pheochromocytoma,
uterine fibromas, and the novel Brx gene. Some of the branch’s
achievements are highlighted below. 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 co-activators. 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 co-activators, proteins that were shown to
participate in a similar co-activator complex in the HIV-1 LTR promoter. They
demonstrated Vpr-mediated glucocorticoid hypersensitivity in several systems,
including interleukin (IL)-12 suppression, and discovered a dominant-negative
Vpr mutant that can eliminate the co-activator 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 fibromyalgia. Nieman also
established that 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 pheochromocytoma.
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 its treatment. The Unit
on Reproductive Endocrinology and Infertility investigated a variety of
clinical reproductive disorders. Studies integral to 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 to demonstration of the major role of Brx in
estrogen receptor and protein kinase signaling systems. |