Lynette Nieman, MD, Acting Chief
The Reproductive Biology and Medicine Branch (RBMB) had a long list of published research achievements in the following areas: glucocorticoid action; interactions between the HPA axis, a major participant in human physiologic and pathophysiologic states, and immune and inflammatory reactions; 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 by translocating into the nucleus and interacting with and sequestering p160 co-activator molecules from the glucocorticoid receptor. They described the involvement of 14-3-3 proteins in the translocation of the activated glucocorticoid receptor. The Section showed that carnitine, an amino acid–derived nutrient essential for mitochondrial function, exerts a positive influence on the glucocorticoid signaling system. They characterized two HIV-1 small accessory proteins, Vpr and Tat, as viral glucocorticoid receptor co-activators, proteins that were shown to be part of a complex with p300/CBP and p160 nuclear receptor co-activators and that 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. In the area of sleep research, the Section found that aging is associated with increases in cortisol and IL-6 secretion that are negatively correlated with the quality of sleep and that women with polycystic ovary syndrome have a 30–fold elevated risk of developing sleep apnea. 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 the Fas ligand by the invasive cytotrophoblast, blocks blastocyst implantation by the invasive cytotrophoblast. 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 severity of the enzymatic and molecular defects; 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 and her colleagues 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 high-resolution SPGR (spoiled gradient) MRI for 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 pheochromocytoma. Investigators developed the 6-[18F]-fluorodopamine PET scan for the diagnostic localization and follow-up of pheochromocytoma as well as the novel use of radiofrequency ablation in its treatment.