Carolyn Bondy, MD, Chief

The mission of the Developmental Endocrinology Branch (DEB) is to investigate diseases that affect the processes of human growth, development, and reproduction. The Branch has focused on genetic as well as on classical endocrine approaches to short stature, childhood obesity, endocrine tumors, Turner’s syndrome, and premature ovarian failure. As part of a multidisciplinary, integrative program, senior staff members are clinicians involved in patient care and clinical fellow training; they participate in weekly ward rounds and clinic conferences. From careful study of patients at the bedside, DEB investigators develop insights that lead to elucidation of the molecular mechanisms of the above disorders and to the development of new diagnostic and therapeutic approaches.

Greti Aguilera’s group, the Section on Endocrine Physiology, focuses on the molecular mechanisms controlling neuroendocrine components of the stress response. She and her colleagues have demonstrated that cAMP stimulates CRH expression at transcriptional and post-transcriptional levels and contributes to limiting the duration of the transcriptional response through the production of cAMP-inducible early repressor (ICER). The Section has also identified novel mechanisms by which vasopressin receptors activate the EGF receptor and the MAP kinase pathway, which in turn induces V1b receptor transcription.

Jeffrey Baron’s Unit on Growth and Development has found evidence that longitudinal bone growth slows with age and eventually stops because stem-like cells in the resting zone of the growth plate have a finite proliferative capacity that is gradually exhausted. Moreover, the loss of proliferative capacity does not appear to be caused by telomere shortening but may instead involve epigenetic mechanisms. The group has also found evidence that, in humans as in other mammals, catch-up growth after a period of linear growth inhibition occurs because growth-inhibiting conditions conserve the finite proliferative capacity of the growth plate chondrocytes.

Carolyn Bondy, who heads the Section on Growth and Metabolism, the Section on Women’s Health Research, and the Unit on Turner’s Syndrome, has shown that young, healthy women with monosomy X or Turner’s syndrome have higher blood pressure and a distinctly more atherogenic lipid profile than age- and body fat–matched women with 46,XX premature ovarian failure. In fact, women with Turner’s syndrome carry atherosclerotic risk factors similar to those carried by men, suggesting that a normal second X chromosome may protect women from atherosclerotic vascular disease through beneficial effects on blood pressure and lipid metabolism. In addition, Bondy and her coworkers discovered a distinct set of psychosocial problems that characterize women with premature ovarian failure, regardless of etiology. They have shown that women with Turner’s syndrome and women with karyotypically normal premature ovarian failure demonstrate identical traits of increased shyness and social anxiety and decreased self-esteem compared with age-matched women with normal ovarian function.

Lawrence Nelson’s Unit on Gynecologic Endocrinology focuses on the pathophysiology and clinical management of spontaneous premature ovarian failure. He and his team have demonstrated a highly significant association between the presence of circulating adrenal cortex autoantibodies and histologically confirmed autoimmune oophoritis, a mechanism of 46,XX spontaneous premature ovarian failure. His group is also investigating the physiology of the normal ovarian aging process. The work has shown that, among the several markers of ovarian aging that have undergone testing, age correlated most strongly with FSH-stimulated serum inhibin B levels. In work investigating the psychological response to the diagnosis of spontaneous premature ovarian failure, the Unit found that women with this condition perceive a need for clinicians to spend more time with them after making the diagnosis and to provide more information about the disorder.

Constantine Stratakis, who heads the Section on Endocrinology and Genetics, and his group focus on clinical and molecular genetics of pituitary and adrenal diseases. They have identified a gene that is mutated in half of patients with Carney complex (CNC), a genetic syndrome that predisposes to the development of multiple tumors of the heart, skin, breast, nervous system, and endocrine glands (thyroid, pituitary, gonads, and adrenal). They found that the gene, which encodes the most common regulatory subunit of protein kinase A (PRKARIA), is expressed in almost all human cells. Protein kinase A is the most important member of an organism’s signaling pathway. Stratakis’s group showed that in the normal physiologic state this regulatory subunit of protein kinase A appears to act as a tumor suppressor. When its action is abolished, however, tumors of various organs develop, as demonstrated by creating two mouse models of the disease that both developed tumors.

Jack Yanovski’s Unit on Growth and Obesity has shown that polymorphisms in the melanocortin 3 receptor partially inactivate the receptor’s function and are correlated with pediatric obesity, particularly in African Americans. The data are the first to demonstrate the importance of this receptor for body weight regulation in humans. A second line of investigation is aimed at the role of brain-derived neurotrophic factor (BDNF) in childhood obesity. The Unit has identified obese individuals with low BDNF levels and is initiating investigations of the genetic basis for this association.