Metabolic vs. hedonic obesity: a conceptual distinction and its clinical implications.

Body weight is determined via both metabolic and hedonic mechanisms. Metabolic regulation of body weight centres around the 'body weight set point', which is programmed by energy balance circuitry in the hypothalamus and other specific brain regions. The metabolic body weight set point has a genetic basis, but exposure to an obesogenic environment may elicit allostatic responses and upward drift of the set point, leading to a higher maintained body weight. However, an elevated steady-state body weight may also be achieved without an alteration of the metabolic set point, via sustained hedonic over-eating, which is governed by the reward system of the brain and can override homeostatic metabolic signals. While hedonic signals are potent influences in determining food intake, metabolic regulation involves the active control of both food intake and energy expenditure. When overweight is due to elevation of the metabolic set point ('metabolic obesity'), energy expenditure theoretically falls onto the standard energy-mass regression line. In contrast, when a steady-state weight is above the metabolic set point due to hedonic over-eating ('hedonic obesity'), a persistent compensatory increase in energy expenditure per unit metabolic mass may be demonstrable. Recognition of the two types of obesity may lead to more effective treatment and prevention of obesity.

Emerging paradigms on glucose management in the intensive care unit.

Hyperglycemia is common in critical illness and leads to increased morbidity and mortality. Controversy exists whether tight glycemic control via intensive insulin therapy can safely and effectively improve outcomes. In this review article, we will sort through the pertinent evidence base to identify salient, yet emergent, paradigms to guide management. To this end, we will discuss underlying biologic mechanisms relevant to hyperglycemia and insulinization in critical illness, summarize results of major randomized controlled clinical trials for glycemic control in the intensive care unit (ICU), and fill in the gaps with necessary information. We will conclude with specific messages, not only reflecting our own clinical experiences, but amenable to implementation in different ICU settings.

Reprogramming cancer cells in endocrine-related tumors: open issues.

Reprogramming technologies have been developed to revert somatic differentiated cells into pluripotent stem cells that can be differentiated into different lineages potentially useful in stem cell therapy. Reprogramming methods have been progressively refined to increase their efficiency, to obtain a cell population suitable for differentiation, and to eliminate viral plasmid which could be responsible for many unwanted side-effects when used in personalized medicine. All these methods are aimed to introduce into the cell genes or mRNAs encoding a set of four transcription factors (OCT- 4, SOX-2, KLF-4 and c-MYC) or a set of three lincRNAs (large intragenic non-coding RNAs) acting downstream of the reprogramming transcription factors OCT-4, SOX-2 and NANOG. Translational clinical applications in human pathologies and in developmental, repair and cancer biology have been numerous. Cancer cells can be, at least in principle, reprogrammed into a normal phenotype. This is a recently raised issue, rapidly advancing in many human tumors, especially endocrine-related cancers, such as breast, prostate and ovarian ca. The present review aims to describe basic phenomena observed in reprogramming tumor cells and solid tumors and to discuss their meaning in human hormone-related cancers. We will also discuss the fact that some of the targeted transcription factors are "normally" activated in a number of physiological processes, such as morphogenesis, hypoxia and wound healing, suggesting an in vivo role of reprogramming for development and homeostasis. Finally, we will review concerns and warnings raised for in vivo reprogramming of human tumors and for the use of induced pluripotent stem cells (iPSCs) in human therapy.

Total parathyroidectomy without autotransplantation for the treatment of secondary hyperparathyroidism associated with chronic kidney disease: clinical and laboratory long-term follow-up.

Forty-six consecutive patients who underwent total parathyroidectomy (tPTX) for hyperparathyroidism associated with end-stage kidney disease (CKD5) in a University Hospital from 1990 to 1999 were included in a long-term observational study. Outcome parameters included symptoms (bone pain, pruritus and muscle weakness evaluated by visual analog scales [VAS]) and laboratory data (intact parathyroid hormone [iPTH], total calcium, and alkaline phosphatase) assessed before, shortly postoperatively and then at a later time point: 40 patients were on maintenance hemodialysis and six on conservative medical therapy. Forty-four patients had four glands removed, while only three glands were found in the remaining two. Perioperative complications consisted of acute symptomatic hypocalcemia in 10 (22%) patients and non-specific complaints in three (7%). No laryngeal nerve palsies occurred. After a median follow-up of eight years, 43 subjects were evaluated: 37 (86%) were cured, three (7%) had persistent and three (7%) recurrent disease. Eleven patients underwent successful renal transplantation and 23 died during the period of observation. iPTH decreased from a mean of 1084+/-505 pg/ml to 120+/-381 pg/ml (p < 0.0001). No subsequent bone fractures, persistent bone pain or disability were reported; this includes patients who later received a functioning renal graft. tPTX was able to correct hyperparathyroidism in most of the patients and was associated with a low long-term relapse rate. iPTH levels remained low in 17 cases without symptoms and no clinically significant side effects. The beneficial effects of tPTX occurred in the majority of patients while renal transplantation was performed in a minority of patients. tPTX should be considered a safe and successful procedure for the treatment of severe secondary hyperparathyroidism associated with chronic kidney disease.

Thyroid hormones and the cardiovascular system: pathophysiology and interventions.

Thyroid dysfunction, however mild, can significantly affect the cardiovascular (CV) system. The effects of thyroid hormones may be viewed as genomic and non-genomic, with the former occurring over a longer time scale and both affecting structural and functional proteins in CV tissue. As the interplay between thyroid function and the CV system becomes elucidated, particularly in the context of a system biology approach, the heart failure phenotype is better understood. Symptomatology is related to disturbance in inotropic and chronotropic function. Moreover, biochemical changes reflected by thyroid function testing with the non-thyroidal illness syndrome can prognosticate and guide therapy in heart failure. In addition, empiric treatment with thyroid hormone analogues or T3 represent emergent and highly controversial interventions.

Withdrawal of corticosteroids in inflammatory bowel disease patients after dependency periods ranging from 2 to 45 years: a proposed method.

BACKGROUND: Even in the biologic era, corticosteroid dependency in IBD patients is common and causes a lot of morbidity, but methods of withdrawal are not well described. AIM: To assess the effectiveness of a corticosteroid withdrawal method. METHODS: Twelve patients (10 men, 2 women; 6 ulcerative colitis, 6 Crohn's disease), median age 53.5 years (range 29-75) were included. IBD patients with quiescent disease refractory to conventional weaning were transitioned to oral dexamethasone, educated about symptoms of the corticosteroid withdrawal syndrome (CWS) and weaned under the supervision of an endocrinologist. When patients failed to wean despite a slow weaning pace and their IBD remaining quiescent, low dose synthetic ACTH stimulation testing was performed to assess for adrenal insufficiency. Multivariate analysis was performed to assess predictors of a slow wean. RESULTS: Median durations for disease and corticosteroid dependency were 21 (range 3-45) and 14 (range 2-45) years respectively. Ten patients (83%) were successfully weaned after a median follow-up from final wean of 38 months (range 5-73). Disease flares occurred in two patients, CWS in five and ACTH testing was performed in 10. Multivariate analysis showed that longer duration of corticosteroid use appeared to be associated with a slower wean (P = 0.056). CONCLUSIONS: Corticosteroid withdrawal using this protocol had a high success rate and durable effect and was effective in patients with long-standing (up to 45 years) dependency. As symptoms of CWS mimic symptoms of IBD disease flares, gastroenterologists may have difficulty distinguishing them, which may be a contributory factor to the frequency of corticosteroid dependency in IBD patients.

Thyroid fine needle aspiration: how to improve clinicians' confidence and performance with the technique.

Studies from single institutions report an acceptable accuracy rate for thyroid fine needle aspiration (FNA). However, FNA accuracy is much lower in many other centers in Europe and the USA and large multicenter studies indicate that the clinicians' confidence in the FNA technique remains low. One explanation for this is that there is an excess of inadequate and indeterminate findings for a follicular nodule at FNA cytology. In a University Hospital with large and qualified experience on thyroid nodule diagnosis, a review of 320 slides with an FNA diagnosis of indeterminate follicular nodule from different minor Italian Hospitals led to a different diagnosis in 61%. Since ancillary thyroid imaging may be overutilized and only a few authors report a proportion of excised nodules lower than 10%, we suspect that use of the FNA procedure is suboptimal. Several techniques are reported to improve the performance of thyroid FNA. Among these are tumor markers and large needle aspiration biopsy (LNAB). Immunodetection of the tumor marker galectin-3 has been evaluated by large multinational studies. Analysis of LNAB specimens reduces the number of inadequate FNA findings, improves the diagnostic determination of indeterminate follicular FNA findings and represents a better substrate for the determination of galectin-3. Therefore, we propose that clinical practice guidelines reflect these adjuvant techniques to thyroid FNA in order to improve selection criteria for thyroid nodule surgery.

Thyroid nodule evaluation: what have we really learned from recent clinical guidelines?

Recent guidelines for the evaluation of thyroid nodules clarify the diagnostic algorithm while also reporting important differences. The performance of fine needle aspiration (FNA) for cytological examination follows serum TSH determination and thyroid ultrasonography. Thyroid scintigraphy is recommended following a low TSH value and/or FNA yielding an indeterminate follicular cytology. The use of thyroid ultrasonography is the source of some controversy: though it is recommended as a principal first test, its real-time use to guide FNA ranges from routine to only following an FNA yielding an inadequate or nondiagnostic cytological result. In clinical practice, the proportion of physicians utilizing ultrasonography, scintigraphy and FNA varies and frequently deviates from recommended guidelines. The development of guidelines is necessary to bring about consistency and optimization to the diagnostic work-up of thyroid nodules. It is likely that novel diagnostic procedures, such as molecular markers, large needle aspiration biopsy and thyroid imaging with tracers beyond conventional radioactive iodine or (99m)Tc pertechnetate, will lead to improved performance and implementation of guidelines.

Progress in the preoperative diagnosis of thyroid nodules: managing uncertainties and the ultimate role for molecular investigation.

The preoperative evaluation of thyroid nodules currently relies on a clinical assessment of risk factors and an algorithm based on imprecise tests. With serum TSH, thyroid ultrasound and fine-needle aspiration (FNA) with or without ultrasound guide, accounting for the routine initial evaluation, indeterminate aspirates remain the major obstacle for confidently advising patients whether to have surgery or not. Recent clinical guidelines have attempted to settle various controversies but many inherent errors of clinical testing result in delayed diagnosis and unnecessary surgery. A better solution may ultimately involve the use of molecular markers of thyroid carcinogenesis but further research is still needed regarding the basic biology of thyroid cancer.

Significance and management of thyroid lesions in lymph nodes as an incidental finding during neck dissection.

BACKGROUND: The incidental discovery of thyroid lesions in lymph nodes during a lymph node dissection performed for a separate primary head and neck tumor is an unusual clinical entity. Its discovery has led to controversy regarding its significance and management. METHODS: We identified five patients over the years 1991-1999 with this finding. All five patients were subsequently treated with a total thyroidectomy and a level VI lymph node dissection. RESULTS: Pathological examination revealed three papillary carcinomas and level VI lymph node metastases in the two patients who had carcinoma in their thyroid glands. All five patients are presently free of their primary and thyroid disease on follow-up examinations. CONCLUSIONS: These patients should be addressed with additional work-up and surgery if metastatic thyroid cancer is documented in the lymph node. We offer a diagnostic algorithm that may aid in further work-up and treatment in these unusual cases.

The influence of intraoperative parathyroid hormone monitoring on the surgical management of hyperparathyroidism.

OBJECTIVE: To examine the role of intraoperative rapid parathyroid hormone (PTH) monitoring in the surgical management of hyperparathyroidism. DESIGN: Thirty-eight-month retrospective review. SETTING: Tertiary care academic medical center. PATIENTS: One hundred consecutive patients undergoing surgery for primary hyperparathyroidism. INTERVENTION: All patients underwent preoperative technetium Tc 99m sestamibi scan localization and intraoperative blood PTH monitoring by means of a rapid (12-minute) immunochemiluminometric assay. MAIN OUTCOME MEASURES: The influence of intraoperative PTH levels on extent of surgical dissection and achievement of postoperative normocalcemia. RESULTS: Intraoperative PTH levels dropped an average of 64%, 75%, and 83% at 5, 10, and 20 minutes, respectively, after excision of all hyperfunctioning parathyroid tissue. A PTH decrease of 46% or more at 10 minutes and 59% or more at 20 minutes after excision of hyperfunctioning tissue was predictive of postoperative normocalcemia. In 79 patients (79%), the sestamibi scan provided accurate preoperative localization; all but 1 of these patients were treated successfully, most often with a limited, gland-specific dissection. In 24 patients with inaccurate, negative, or misleading preoperative sestamibi scans, 23 (96%) were treated successfully with the use of the intraoperative PTH assay. CONCLUSIONS: The rapid intraoperative PTH assay accurately predicts postoperative success in patients with primary hyperparathyroidism. The rapid PTH assay allows for greater confidence in performing limited dissections in well-localized uniglandular disease. In cases of inaccurate preoperative localization, the rapid PTH assay directly affects surgical decision making and provides greater confidence in determining when surgical success has been achieved.

Diagnostic accuracy of fine-needle aspiration and frozen section in nodular thyroid disease.

OBJECTIVE: To assess the diagnostic accuracy of fine-needle aspiration (FNA) and frozen section (FS) in nodular thyroid disease. SETTING: Tertiary care academic medical center. STUDY DESIGN: Retrospective review of 139 consecutive patients undergoing surgery for nodular thyroid disease. FNA and FS sensitivity, specificity, and accuracy were calculated with respect to permanent section histology. RESULTS: Among 63 patients with an FNA interpreted as either benign (n = 38) or malignant (n = 25), FNA was accurate (sensitivity 89%, specificity 97%, accuracy 94%). FS identified only one case of carcinoma missed by FNA. Among 76 patients with a "suspicious" FNA, FS was reasonably accurate (sensitivity 67%, specificity 100%, accuracy 89%), but was deferred in 50% of cases. CONCLUSION: Given high FNA accuracy, more selective use of FS is suggested. SIGNIFICANCE: The study results will assist with intra-institutional patient counseling and intraoperative decision-making with respect to FNA and FS results in patients with nodular thyroid disease.

A normal variant on Tl-201 and Tc-99m MIBI whole-body imaging: the superior right atrial wall (auricle) and superoanterior right ventricular wall are often seen as mediastinal lesions.

PURPOSE: The authors have often observed on Tl-201 and Tc-99m sestamibi (MIBI) scans in patients with thyroid cancer a small focus of increased uptake in the right midparasternal region (focus A) or sometimes in the lower mid chest at the level of the lower sternum (focus B) just inferomedial to focus A. The objective of this study was to assess the frequency of this finding on Tl-201 MIBI studies, to assess the incidence of true pathologic lesions corresponding to these foci, and to identify their nature. MATERIALS AND METHODS: One hundred ten whole body Tl-201 studies using 4 mCi (148 MBq) and 84 MIBI studies using 20 mCi (740 MBq: first-pass, planar, and SPECT images) were reviewed. The appearance of either focus A or focus B on three orthogonal SPECT images was correlated with an atlas of cross-sectional anatomy and computed tomography. If focus A was seen on the immediate static image (obtained at the end of the first-pass acquisition without moving the patient), this image was coregistered with a selected image from the first-pass study showing the superior vena cava and also with another selected image showing the ascending aorta. RESULTS: Focus A was seen in 40% of Tl-201 scans and in 49% of MIBI scans, whereas focus B was seen in 20% of Tl-201 scans and 39% of MIBI scans. On correlation of the SPECT images with a cross-sectional anatomy atlas, focus A and focus B invariably corresponded to the superior portion of the right auricle and basal superoanterior right ventricular wall, respectively. These myocardial regions are prominent and sometimes appear as discrete foci because they are considerably thicker than other parts of the right atrial and right ventricular muscle, respectively, and because they are seen partly end-on in the anterior projection. CONCLUSIONS: The superior portion of the right auricle and basal superoanterior right ventricular myocardium often appear as isolated foci on whole-body Tl-201 and MIBl scans. Neither focus should be interpreted as a metastatic lesion in patients with possible cancer or as an ectopic parathyroid adenoma in patients with hyperparathyroid disease.

Combined calcitriol-pamidronate therapy for bone hyperresorption in spinal cord injury.

OBJECTIVE: To determine the biochemical effects of combined calcitriol-pamidronate therapy on bone hyperresorption in patients with spinal cord injury (SCI). METHODS: This was a retrospective study of 21 SCI inpatients (4 women and 17 men, mean age 34 years) treated for bone hyperresorption. Initial treatment was 0.5 microg oral calcitriol once daily and 1,250 mg CaCO3 twice a day (1000 mg elemental calcium/day). On days 4 through 6 following the initial treatment, patients received 30 mg pamidronate intravenously once daily (total of 3 doses). Urinary N-telopeptide (NTx) and calcium excretion rates, and serum parathyroid hormone (PTH), 25-hydroxyvitamin D (25-D), 1,25-dihydroxyvitamin D (1,25-D), calcium, and phosphorus levels were measured within 2 weeks prior to and 2 weeks following pamidronate therapy. RESULTS: Patients demonstrated increased urinary NTx and calcium excretion, indicative of bone hyperresorption, and suppressed PTH and 1,25-D levels as early as 9 days post-SCI. Combined calcitriol-pamidronate therapy decreased urinary NTx and calcium excretion by 71% (P < .001) and 73% (P < .001), respectively. This therapy also increased serum levels of PTH (P <.05) and 1,25-D (P < .005). Post-pamidronate hypocalcemia or hypophosphatemia was observed in 44% (P < .01) or 53% (P < .01), respectively. CONCLUSION: Combined calcitriol-pamidronate therapy significantly inhibited bone hyperresorption in SCI patients.

Biochemical response to treatment of bone hyperresorption in chronically critically ill patients.

STUDY OBJECTIVE: The chronically critically ill (CCI) are a subgroup of critically ill patients who have survived an acute critical illness but remain profoundly debilitated and ventilator dependent. We have previously shown that CCI patients have a very high prevalence of bone hyperresorption. The objective of this present study was to determine the biochemical response of bone hyperresorption in CCI patients to treatment with either calcitriol alone or calcitriol and pamidronate. DESIGN: Retrospective survey. SETTING: Respiratory care step-down unit (RCU) at a tertiary-care teaching hospital. PATIENTS: Fifty-five ventilator-dependent CCI patients transferred from ICUs within the same institution who had elevated urine N-telopeptide (NTx) levels at RCU admission, who were treated with either calcitriol alone (n = 44) or calcitriol and pamidronate (n = 11), and who had urine NTx levels remeasured following treatment. INTERVENTION: None. MEASUREMENTS AND RESULTS: Patients treated with calcitriol alone had a significant reduction in serum parathyroid hormone (PTH; 93+/-145 pg/mL vs 40+/-28 pg/mL; p = 0.02) but not in urinary NTx (187+/-146 nmol bone collagen equivalents [BCE]/mmol creatinine [Cr] vs. 178+/-123 nmol BCE/mmol Cr, p = 0.59). In contrast, patients treated with both calcitriol and pamidronate had a significant decrease in urine NTx at follow-up (329+/-238 to 100+/-85 nmol BCE/mmol Cr; p<0.01) but not in serum PTH (36+/-29 to 53+/-51 pg/mL; p = 0.44). CONCLUSION: The bone hyperresorption of CCI patients is PTH independent and biochemically responds to treatment with calcitriol and pamidronate but not calcitriol alone.

Hypotestosteronemia in chronically critically ill men.

OBJECTIVE: To determine the prevalence of hypotestosteronemia in chronically critically ill (CCI) men. DESIGN: Prevalence survey. SETTING: Step-down respiratory care unit (RCU) at a tertiary care teaching hospital. PATIENTS: Thirty ventilator-dependent CCI men transferred from intensive care units (ICUs) within the same institution. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Total testosterone and bioavailable testosterone (bioT) concentrations were measured within 48 hrs of RCU admission. Patients were hospitalized a median of 40 days (range, 9-185 days) before RCU admission, with a median ICU length of stay of 25 days (range, 9-177 days). At RCU admission, total testosterone concentrations averaged 104+/-96 ng/dL, with average bioT concentrations of 19+/-20 ng/dL (16+/-9% of total testosterone). Twenty-nine of the 30 patients (96%) had bioT concentrations well below the lower limit of normal for their age range. bioT concentrations, expressed as a percentage of the normal mean for each patient's age range, were positively correlated with the number of days that the patient was in the ICU before transfer to the RCU (n = 30, r2 = .17, p = .025). However, if the single patient who remained in the ICU for 177 days was excluded, this correlation disappeared (n = 29, r2 = .07, p = .09). No other relationship was found between bioT concentrations and any other variable, including type of patient, ICU length of stay, reason for either initial admission to the ICU or prolonged mechanical ventilation, type of nutritional support, or use of dopamine. CONCLUSIONS: CCI men have a very high prevalence of hypotestosteronemia, which may impede their recuperation and rehabilitation. Further studies are needed to determine whether additional pharmacologic treatment with testosterone can improve the recovery of these patients.

Bone hyperresorption is prevalent in chronically critically ill patients.

STUDY OBJECTIVE: Chronically critically ill (CCI) patients are primarily elderly people who have survived a life-threatening episode of sepsis but remain profoundly debilitated and ventilator dependent. The objective of this study was to determine the prevalence of bone hyperresorption and parathyroid hormone (PTH)-vitamin D axis abnormalities in these patients. DESIGN: Prevalence survey. SETTING: Respiratory care step-down unit (RCU) at a tertiary care teaching hospital. PATIENTS: Forty-nine ventilator-dependent CCI patients transferred from ICUs within the same institution. INTERVENTION: None. MEASUREMENTS AND RESULTS: N-telopeptide (NTx) levels in 24-h urine collections and serum intact PTH, 25-vitamin D, and 1,25-vitamin D levels were measured within 48 h of RCU admission. Patients were hospitalized a median of 30 days before RCU admission. Four patients (9%) had normal NTx and PTH levels. Forty-five patients (92%) had elevated urine NTx levels consistent with bone hyperresorption. Nineteen patients (42% of total patients) had elevated PTH levels consistent with predominant vitamin D deficiency, 4 patients (9%) had suppressed PTH levels consistent with predominant hyperresorption from immobilization, and 22 patients (49%) had normal PTH levels consistent with an overlap of both vitamin D deficiency and immobilization. There were no differences in vitamin D metabolites among these groups. CONCLUSIONS: CCI patients have a high prevalence of bone hyperresorption in which PTH levels may clarify the cause. Further studies will determine the efficacy and cost-effectiveness of routine NTx and PTH screening in these patients and the role of vitamin D and antiresorptive therapies.

Cytologic findings in the differential diagnosis of C-cell hyperplasia and medullary carcinoma by fine needle aspiration. A case report.

BACKGROUND: The cytologic features of C-cell hyperplasia of the thyroid have not been previously addressed in the literature. We describe the first case, to our knowledge, of C-cell hyperplasia that was suggested by fine needle aspiration. CASE: Cellular material was obtained from a nonnodular region of the thyroid gland in a 67-year-old male with chronic diarrhea, unexplained elevated serum calcitonin, no clinically detectable thyroid mass and no known medical or family history of an endocrine disorder. Aspiration yielded a scant bimodal cell population composed of benign follicular cells and a second population of larger cells, later confirmed as C-cells via immunohistochemistry. Although the diagnosis of medullary carcinoma was entertained, the absence of a discrete mass clinically and the presence of two interspersed, distinct cell populations suggested the alternate diagnosis, C-cell hyperplasia, which was confirmed by subsequent thyroidectomy. CONCLUSION: C-cell hyperplasia can mimic medullary carcinoma biochemically, and this case suggests the possible role of fine needle aspiration of the thyroid to distinguish between the two. In patients with elevated serum calcitonin and absence of a discrete thyroid nodule, the finding of clusters of calcitonin-positive cells intermixed with normal follicular cells by fine needle aspiration may provide a means of making a presurgical diagnosis of C-cell hyperplasia.

Hypothalamic-pituitary axis dysfunction in critically ill patients with a low free thyroxine index.

The purpose of this study is to investigate the association of hypothalamic-pituitary axis abnormalities with the free thyroxine index (FTI) in critically ill patients. Fourteen critically ill patients and twenty healthy volunteers were studied using combined anterior pituitary gland testing with CRF, GHRH, TRH, and GnRH. The subjects were grouped as follows: I-healthy volunteers; II-sick/normal FTI; and III-sick/low FTI. Serial measurements of hormones were performed over a two-hour interval and the following parameters were measured: baseline level, response amplitude and time to maximal response. Response velocities and area-under-the-curves (integrated responses) were also computed. Group III had a longer mean ICU duration prior to testing than group II. Urinary cortisol, serum cortisol and serum PRL levels were elevated in groups II and III. However, group III had lower baseline ACTH levels, slower ACTH and TSH response velocities and decreased PRL integrated responses. Cortisol response parameters were similar between groups II and III. There were no differences in LH, FSH or GH response velocities or integrated responses among the 3 groups. These data confirm that critically ill patients develop hyperprolactinemia and hypothalamic-pituitary-adrenal axis activation but when a low FTI exists, a plurality of changes occur reflected by attenuated PRL, TSH and ACTH responses despite unaffected adrenal cortisol output.