Bornstein SR, Stratakis CA, Chrousos GP.  Adrenocortical tumors: recent advances in basic concepts and clinical management.  Ann Intern Med. 1999;130:759-771.

     Adrenocortical masses are among the most common tumors in humans.  However, only a small proportion of these tumors cause endocrine diseases (such as primary hypoaldosteronism, hypercortisolism, hyperandrogenism, or hyperestrogenism), and less than 1% are malignant.  In recent years, several of the molecular and cellular mechanisms involved in adrenal tumorigenesis have been unraveled.  As a result, alterations in intercellular communication, local production of growth factors and cytokines, and aberrant expression of ectopic receptors on adrenal tumor cells have been implicated in adrenal cell growth, hyperplasia, tumor formation, and autonomous hormone production.  Genetic and chromosomal abnormalities, including several chromosomal loci and the genes coding for p53, p57, and insulin-like growth factor II have been reported in adrenal tumors.  In addition, chromosomal markers have been identified in several familial syndromes associated with adrenal tumors; these include menin, which is responsible for multiple endocrine neoplasia type I, and the hybrid gene that causes glucocorticoid-remediable hyperaldosteronism.  Algorithms for endocrine testing and imaging procedures are now available to codify screening for, confirmation of, and differentiation of causes of primary hyperaldosteronism and the Cushing syndrome.   Improved radiologic, computerized radiologic, and magnetic resonance imaging techniques, as well as selective catheritization studies, are useful in locating adrenal tumors and in distinguishing between benign and malignant legions and between functional and nonfunctional nodules.  Finally, recent refinements in the field of minimally invasive general surgery have made laparoscopic adrenalectomy the method of choice for removing adrenal tumors; this type of surgery allows shorter hospital stays, lower morbidity rates, and faster recovery. 

Ehrhart-Bornstein M, et al. Intraadrenal interactions in the regulation of adrenocortical steroidogenesis. Endocr Rev. 1998 Apr; 19(2): 101-143.
Willenberg H, Stratakis CA, et al. Aberrant interleukin-1 receptor in a cortisol-secreting adrenal adenoma causing Cushing´s syndrome. N Engl J Med. 1998 Jul 2; 339(1): 27-31.

     Currently, the major focus of our clinical studies is the regulation and
functioning of the human stress systems, hypothalamic-pituitary-adrenal axis, and
sympathetic/sympathoadrenal nervous system in disease. Particularily, the
interaction of the two systems and the interaction with the immune system and
the metabolic system is studied. Pertubations and alterations are analyzed in
patients with acute inflammation, immunosuppression, diabetes, obesity, and a
great variety of stress-related disorders.

Plasma Leptin Levels are Increased in Survivors of Acute Sepsis: Associated Loss of Diurnal Rhythm in Cortisol and Leptin Secretion

S.R. Bornstein, J. Licinio, R. Tauchnitz, L. Engelmann, AB Negrão, P. Gold, G.P. Chrousos.  J Clin Endocrinol Metab 1998; 83:280-283.

Abstract: Recent animal and human studies have suggested that leptin secretion is closely linked to the functions of the hypothalamic-pituitary-adrenal (HPA) axis and the immune system, both of which are crucial in influencing the course and outcome of critical illness. Therefore, we measured basal plasma leptin levels and examined the circadian secretion of leptin, in parallel with the hormones of the HPA axis and a key cytokine, interleukin-6 (IL-6), in critically ill patients with acute sepsis. Sixteen critically ill patients from the University of Leipzig Intensive Care Unit were recruited for this study. All of these patients fulfilled the standard diagnostic criteria for sepsis. Plasma leptin levels were measured in all patients and controls at 09:00. In addition, in a subgroup of eight critically ill patients and all of the nine controls , plasma leptin, cortisol, ACTH and interleukin-6 concentrations were measured every 4 hours for 24 hours. Interleukin 6 was analysed in the same group at 09:00. Mean plasma leptin levels were three-fold higher (18.9 ± 4.5 ng/ml) in critically ill patients than controls (3.8 ± 1.0 ng/ml, p<0.05). Similarly, ACTH levels were lower (7.8 ± 3.4 pmol/l) in patients than in controls (17.1±1.5 pmol/l, p<.001), while plasma cortisol levels were increased (947.6 ±144 nmol/l) in patients compared to controls (361.1±29, p< 0.001). Plasma interleukin-6 was markedly elevated in all patients with sepsis (1238.0±543.1 pg/ml) vs controls (6.4 ±1.7 pg/ml, p<0.001). The controls exhibited a nyctohemeral fluctuation in plasma leptin levels with peak levels at 23:00; in contrast, in septic patients, the nocturnal rise of leptin was abolished. In healthy controls, plasma leptin and cortisol had reciprocal circadian rhythms with high nocturnal leptin levels and low nocturnal cortisol concentrations; in critically ill patients, this relation was abolished. Mean leptin levels were three-fold higher in patients who survived the septic episode (25.5±6.2, n=10) than in non-survivors (8.0 ±3.7, n=6, p<0.01), while IL-6 levels were ten-fold lower in survivors (176.6±56.5) than in non-survivors (2299.4 ±788.7, p <0.01). In addition to its function as an anti-obesity factor, leptin may play a role in a severe stress state such as acute sepsis. Leptin, along with IL-6, may be of prognostic value for the outcome of acute sepsis.

Chronic Effects of a Nonpeptide Corticotropin-releasing Hormone Type I-Receptor Antagonist on Pituitary-Adrenal Function, and Body Weight and Metabolic Regulation

SR Bornstein, EL Webster, DJ Torpy, SJ Richman, N Mitsiades, M Jgel, DB Lewis, KC Rice, HG. Joost, M Tsokos, GP Chrousos. Endocrinology 1998; 139:1546-1555.

Abstract: Corticotropin releasing hormone (CRH), the principal regulator of the hypothalamic-pituitary-adrenal (HPA) axis and modulator of autonomic nervous system activity, also participates in the regulation of appetite and energy expenditure. Antalarmin, a pyrrolopyrimidine compound antagonizes CRH type-1 receptor mediated effects of CRH, including pituitary ACTH release, stress behaviors and acute inflammation. We administered antalarmin chronically to evaluate its effects on HPA axis function and metabolic status. Adult male rats were treated twice daily with 20 mg/kg of intraperitoneal antalarmin or placebo over 11 days. The animals were weighed, plasma ACTH, corticosterone, leptin, and blood glucose levels were determined and morphometric analyses were performed to determine adrenal size and structure, including weighing, histochemistry, immunohistochemistry, and electron microscopy. Leptin mRNA expression in peripheral fat was analyzed by Northern blot. Antalarmin decreased plasma ACTH and corticosterone concentrations (ACTH mean ± SD 2.62 ± .063 pg/ml, corticosterone 10.21± 1.80 µg/dl) vs respectively, ACTH= 5.3 ± 2.0, p<0.05, and 57.02 ± 8.86, p<0.01). Antalarmin had no effect on body weight, plasma leptin or blood glucose concentrations or fat cell leptin mRNA levels. The width of the adrenal cortex of animals treated with antalarmin was reduced without atrophy of the gland. On the ultrastructural level, adrenocortical cells were in a hypofunctional state characterized by reduced vascularization, increased content of lipid droplets, and tubulovesicular mitochondria with fewer inner membranes. Apoptotic rate was markedly increased in the outer zona fasciculata of animals treated with the antagonist (26.6% ±3.58) compared to placebo-treated controls (6.8% ± .906). We conclude that chronic adminstration of antalarmin does not affect body weight, carbohydrate metabolism, or leptin expression, while it does supress adrenocortical function mildly, without evidence of causing atrophy. These results are promising for future uses of such an antagonist in the clinic.