In February 1999, a workshop was held in Cortina, Italy to develop a consensus defining the criteria for cure of acromegaly. The workshop was sponsored by the University of Brescia and hosted by the Italian Society of Endocrinology. Invited international participants included endocrinologists, neurosurgeons, and radiotherapists skilled in the management of acromegaly. This statement summarizes the consensus achieved in these discussions.

Genetic mutations in the leptin pathway can be a cause of human obesity. It is still unknown whether leptin can be effective in the treatment of fully established morbid obesity and its endocrine and metabolic consequences in adults. To test the hypothesis that leptin has a key role in metabolic and endocrine regulation in adults, we examined the effects of human leptin replacement in the only three adults identified to date who have genetically based leptin deficiency. We treated these three morbidly obese homozygous leptin-deficient adult patients with recombinant human leptin at low, physiological replacement doses in the range of 0.01-0.04 mg͞kg for 18 months. Patients were hypogonadal, and one of them also had type 2 diabetes mellitus. We chose the doses of recombinant methionyl human leptin that would achieve normal leptin concentrations and administered them daily in the evening to model the normal circadian variation in endogenous leptin. The mean body mass index dropped from 51.2 ؎ 2.5 (mean ؎ SEM) at baseline to 26.9 ؎ 2.1 kg͞m 2 after 18 months of treatment, mainly because of loss of fat mass. We document here that leptin replacement therapy in leptin-deficient adults with established morbid obesity results in profound weight loss, increased physical activity, changes in endocrine function and metabolism, including resolution of type 2 diabetes mellitus and hypogonadism, and beneficial effects on ingestive and noningestive behavior. These results highlight the role of the leptin pathway in adults with key effects on the regulation of body weight, gonadal function, and behavior.T he increasing rates of obesity and consequent morbidity represent a major epidemic worldwide and threaten to bankrupt health care systems (1-3). While prevention is of great importance, it is medically relevant to identify biological pathways with the potential to treat obesity and related disorders, particularly in adults with fully established obesity and comorbid conditions, such as type 2 diabetes mellitus. Leptin, the product of the ob gene, plays a central role in the regulation of food intake and energy expenditure (4). Mutations in the leptin pathway can be a cause of human obesity (5-7). In children with complete leptin deficiency and who are still in the process of gaining weight and developing obesity, leptin replacement therapy can lead to substantial weight reduction (8,9).It is still unknown whether the leptin pathway is relevant to the treatment of established morbid obesity and its endocrine and metabolic consequences in adults. We addressed this question by treating three homozygous leptin-deficient adults with morbid obesity. Morbid obesity had been fully established for two to four decades in those patients, and they had been at a stable (but very high) weight for Ͼ10 years. They were hypogonadal, and one of them had type 2 diabetes mellitus. We report here the results of the first 18 months of replacement therapy with recombinant human leptin, showing that leptin is highly effective in dramatically reducing...

Mean plasma GH concentrations are controlled by the frequency, amplitude, and duration of underlying GH secretory bursts as well as by the half-life of endogenous GH. We investigated the specific mechanisms that subserve the clinically recognized negative effects of age and adiposity on mean serum GH concentrations. To this end, 21 healthy men, aged 21-71 yr, who were of nearly normal body weight underwent blood sampling at 10-min intervals for 24 h. Deconvolution analysis was used to estimate specific features of GH secretion and clearance. Compared to younger men, the older tertile of men had significant reductions in 1) GH secretory burst frequency, 2) the half-life of endogenous GH, and 3) the daily GH secretory rate, but not 4) GH secretory burst half-duration, amplitude, or mass. Linear regression analysis disclosed that age was a major negative statistical determinant of GH secretory burst frequency (r = -0.80; P = 0.005) and endogenous GH half-life (r = -0.70; P = 0.024). Body mass index, an indicator of relative obesity, was a significant negative correlate of GH half-life (P = 0.045) and GH secretory burst amplitude (P = 0.031). Age and body mass index each correlated negatively with the daily GH secretion rate (P = 0.0031 and P = 0.027, respectively), and together accounted for more than 60% of the variability in 24-h GH production rates (r = -0.78; P = 0.00056). On the average, for a normal body mass index, each decade of increasing age attenuated the GH production rate by 14% and the GH half-life by 6%. Conversely, each unit increase in body mass index, at a given age, reduced the daily GH secretion rate by 6%. We conclude that age and relative adiposity are distinct and specific correlates of individual attributes of GH secretion and clearance in men.

Both stress-system activation and melancholic depression are characterized by fear, constricted affect, stereotyped thinking, and similar changes in autonomic and neuroendocrine function. Because norepinephrine (NE) and corticotropin-releasing hormone (CRH) can produce these physiological and behavioral changes, we measured the cerebrospinal fluid (CSF) levels each hour for 30 consecutive hours in controls and in patients with melancholic depression. Plasma adrenocorticotropic hormone (ACTH) and cortisol levels were obtained every 30 min. Depressed patients had significantly higher CSF NE and plasma cortisol levels that were increased around the clock. Diurnal variations in CSF NE and plasma cortisol levels were virtually superimposable and positively correlated with each other in both patients and controls. Despite their hypercortisolism, depressed patients had normal levels of plasma ACTH and CSF CRH. However, plasma ACTH and CSF CRH levels in depressed patients were inappropriately high, considering the degree of their hypercortisolism. In contrast to the significant negative correlation between plasma cortisol and CSF CRH levels seen in controls, patients with depression showed no statistical relationship between these parameters. These data indicate that persistent stress-system dysfunction in melancholic depression is independent of the conscious stress of the disorder. These data also suggest mutually reinforcing bidirectional links between a central hypernoradrenergic state and the hyperfunctioning of specific central CRH pathways that each are driven and sustained by hypercortisolism. We postulate that ␣-noradrenergic blockade, CRH antagonists, and treatment with antiglucocorticoids may act at different loci, alone or in combination, in the treatment of major depression with melancholic features. M ajor depression is a complex disorder with an estimated lifetime prevalence of 15% in women and 8% in men (1). Depression is the main cause of suicide: Ϸ70% of all suicides are attributed to untreated depression. Studies in the United States suggest that, at any given time, Ϸ2-3% of the population is hospitalized or seriously impaired by affective illness. The World Health Organization has declared major depression as the single largest cause of morbidity for women and the leading cause of disability worldwide.The current standard diagnostic instrument for psychiatry, the Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. (DSM-IV) (2), lists two subtypes of major depression, melancholic and atypical. The features of melancholic depression include insomnia (most often early morning awakening), loss of appetite, weight loss, inappropriate guilt, and lack of pleasure (anhedonia). The second major subtype is major depression with atypical features, characterized in part by hypersomnia, hyperphagia, lethargy, and fatigue. The subclassification of depression provides direction for the appropriate choice of antidepressant medication. Studies in identical twins show a significantly higher concordance for ...

To investigate patterns of endogenous hormone release, we have proposed a biophysical model in which measured hormone concentrations at any given instant reflect the operation of a suitable cumulation function (secretory input) convolved with an appropriate elimination mechanism (metabolic clearance). The cumulation function underlying a macroscopic hormone secretory burst can be represented by a random (Gaussian) distribution of instantaneous molecular secretory rates, which are centered with some finite and determinable standard deviation about a particular moment in time. The hormone elimination mechanism is described by a mono-or biexponential clearance function. The resultant convolution integral is solved by iterative nonlinear leastsquares parameter estimation, in which all plasma hormone concentrations and their variances are considered simultaneously. Experiments with human endocrine time series revealed that the spontaneous secretory patterns of any of multiple distinct anterior pituitary hormones (luteinizing hormone, follicle-stimulating hormone, growth hormone, prolactin, thyrotropin, and adrenocorticotropic hormone) can be described effectively by this parsimonious model. In addition, endogenous hormone disappearance rates determined by deconvolution agreed well with those reported earlier that were determined after exogenous hormone injections. Moreover, this model predicted that durations of underlying secretory impulses are extremely brief; i.e., the standard deviations of the Gaussian distributions of instantaneous secretory rates range from 4.5 min (luteinizing hormone) to 16 min (growth hormone) compared to plasma hormone concentration peaks of 90-140 min in duration. Accordingly, we conclude that observed physiological patterns of fluctuating plasma hormone concentrations can be accounted for by distinct, highly delimited, random bursts of hormone release separated by intervals of secretory quiescence.Endocrine glands are believed to signal their remote target organs by an intermittent rather than a continuous mode of hormone secretion (1, 2). This presumptively episodic pattern of agonist release might avoid down-regulation of target tissue responses, which could otherwise occur if cells were exposed to unvarying concentrations of a trophic agent. Despite this general inference, few if any analyses have addressed the following physiological question: What is the nature of underlying secretory events that are translated into episodic changes in circulating hormone concentrations?In the present work, we suggest that the secretion of biological macromolecules by an endocrine gland comprises a population of random instantaneous molecular release events, with finite probable amplitude, standard deviation, and temporal position. Since metabolic removal mechanisms operate simultaneously with hormone secretion, these two processes are related by a convolution integral, which can be solved by iterative nonlinear least-squares parameter estimation in which all plasma hormone concentrations an...

To elucidate the role of leptin in regulating neuroendocrine and metabolic function during an acute fast, six to eight healthy, lean men were studied under four separate conditions: a baseline fed state and three 72-hour fasting studies with administration of either placebo, low-dose recombinant-methionyl human leptin (r-metHuLeptin), or replacement-dose r-metHuLeptin designed to maintain serum leptin at levels similar to those in the fed state. Replacement-dose r-metHuLeptin administered during fasting prevents the starvation-induced changes in the hypothalamic-pituitary-gonadal axis and, in part, the hypothalamic-pituitary-thyroid axis and IGF-1 binding capacity in serum. Thus, in normal men, the fall in leptin with fasting may be both necessary and sufficient for the physiologic adaptations of these axes, which require leptin levels above a certain threshold for activation. In contrast to findings in mice, fasting-induced changes in the hypothalamic-pituitary-adrenal, renin-aldosterone, and growth hormone–IGF-1 axes as well as fuel utilization may be independent of leptin in humans. The role of leptin in normalizing several starvation-induced neuroendocrine changes may have important implications for the pathophysiology and treatment of eating disorders and obesity

Integrative neuroendocrine control of the gonadotropic and somatotropic axes in childhood, puberty, and young adulthood proceeds via multiple convergent and divergent pathways in the human and experimental animal. Emerging ensemble concepts are required to embody independent, parallel, and interacting mechanisms that subserve physiological adaptations and pathological disruption of reproduction and growth. Significant advances in systems biology will be needed to address these challenges.

Body composition exhibits marked variations across the early human lifetime. The precise physiological mechanisms that drive such developmental adaptations are difficult to establish. This clinical challenge reflects an array of potentially confounding factors, such as marked intersubject differences in tissue compartments; the incremental nature of longitudinal intrasubject variations in body composition; technical limitations in quantitating the unobserved mass of mineral, fat, water, and muscle ad seriatim; and the multifold contributions of genetic, dietary, environmental, hormonal, nutritional, and behavioral signals to physical and sexual maturation. From an endocrine perspective (reviewed here), gonadal sex steroids and GH/IGF-I constitute prime determinants of evolving body composition. The present critical review examines hormonal regulation of body composition in infancy, childhood, and puberty.