The Use of Recombinant Human Growth Hormone to Protect Against Muscle Weakness in Patients Undergoing Anterior Cruciate Ligament Reconstruction: A Pilot, Randomized Placebo-Controlled Trial.

BACKGROUND: Anterior cruciate ligament (ACL) tears are common knee injuries. Despite undergoing extensive rehabilitation after ACL reconstruction (ACLR), many patients have persistent quadriceps muscle weakness that limits their successful return to play and are also at an increased risk of developing knee osteoarthritis (OA). Human growth hormone (HGH) has been shown to prevent muscle atrophy and weakness in various models of disuse and disease but has not been evaluated in patients undergoing ACLR. HYPOTHESIS: Compared with placebo treatment, a 6-week perioperative treatment course of HGH would protect against muscle atrophy and weakness in patients undergoing ACLR. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: A total of 19 male patients (aged 18-35 years) scheduled to undergo ACLR were randomly assigned to the placebo (n = 9) or HGH (n = 10) group. Patients began placebo or HGH treatment twice daily 1 week before surgery and continued through 5 weeks after surgery. Knee muscle strength and volume, patient-reported outcome scores, and circulating biomarkers were measured at several time points through 6 months after surgery. Mixed-effects models were used to evaluate differences between treatment groups and time points, and as this was a pilot study, significance was set at P < .10. The Cohen d was calculated to determine the effect size. RESULTS: HGH was well-tolerated, and no differences in adverse events between the groups were observed. The HGH group had a 2.1-fold increase in circulating insulin-like growth factor 1 over the course of the treatment period (P < .05; d = 2.93). The primary outcome measure was knee extension strength, and HGH treatment increased normalized peak isokinetic knee extension torque by 29% compared with the placebo group (P = .05; d = 0.80). Matrix metalloproteinase-3 (MMP3), which was used as an indirect biomarker of cartilage degradation, was 36% lower in the HGH group (P = .05; d = -1.34). HGH did not appear to be associated with changes in muscle volume or patient-reported outcome scores. CONCLUSION: HGH improved quadriceps strength and reduced MMP3 levels in patients undergoing ACLR. On the basis of this pilot study, further trials to more comprehensively evaluate the ability of HGH to improve muscle function and potentially protect against OA in patients undergoing ACLR are warranted. REGISTRATION: NCT02420353 ( ClinicalTrials.gov identifier).

A machine learning approach to predict early outcomes after pituitary adenoma surgery.

OBJECTIVEPituitary adenomas occur in a heterogeneous patient population with diverse perioperative risk factors, endocrinopathies, and other tumor-related comorbidities. This heterogeneity makes predicting postoperative outcomes challenging when using traditional scoring systems. Modern machine learning algorithms can automatically identify the most predictive risk factors and learn complex risk-factor interactions using training data to build a robust predictive model that can generalize to new patient cohorts. The authors sought to build a predictive model using supervised machine learning to accurately predict early outcomes of pituitary adenoma surgery.METHODSA retrospective cohort of 400 consecutive pituitary adenoma patients was used. Patient variables/predictive features were limited to common patient characteristics to improve model implementation. Univariate and multivariate odds ratio analysis was performed to identify individual risk factors for common postoperative complications and to compare risk factors with model predictors. The study population was split into 300 training/validation patients and 100 testing patients to train and evaluate four machine learning models using binary classification accuracy for predicting early outcomes.RESULTSThe study included a total of 400 patients. The mean ± SD patient age was 53.9 ± 16.3 years, 59.8% of patients had nonfunctioning adenomas and 84.7% had macroadenomas, and the mean body mass index (BMI) was 32.6 ± 7.8 (58.0% obesity rate). Multivariate odds ratio analysis demonstrated that age < 40 years was associated with a 2.86 greater odds of postoperative diabetes insipidus and that nonobese patients (BMI < 30) were 2.2 times more likely to develop postoperative hyponatremia. Using broad criteria for a poor early postoperative outcome-major medical and early surgical complications, extended length of stay, emergency department admission, inpatient readmission, and death-31.0% of patients met criteria for a poor early outcome. After model training, a logistic regression model with elastic net (LR-EN) regularization best predicted early postoperative outcomes of pituitary adenoma surgery on the 100-patient testing set-sensitivity 68.0%, specificity 93.3%, overall accuracy 87.0%. The receiver operating characteristic and precision-recall curves for the LR-EN model had areas under the curve of 82.7 and 69.5, respectively. The most important predictive variables were lowest perioperative sodium, age, BMI, highest perioperative sodium, and Cushing's disease.CONCLUSIONSEarly postoperative outcomes of pituitary adenoma surgery can be predicted with 87% accuracy using a machine learning approach. These results provide insight into how predictive modeling using machine learning can be used to improve the perioperative management of pituitary adenoma patients.

Correction to: Criteria for the definition of Pituitary Tumor Centers of Excellence (PTCOE): A Pituitary Society Statement.

The original version of this article unfortunately contained an affiliation error in 'Collaborators for The Pituitary Society, Expert Group on Pituitary Tumors' section. Dr. Misa Pfeifer is affiliated with Medical Faculty, University of Ljubljana, Slovenia and the correct email address to contact is misa.pfeifer@gmail.com.

Korsakoff syndrome from retrochiasmatic suprasellar lesions: rapid reversal after relief of cerebral compression in 4 cases.

Korsakoff syndrome is a chronic memory disorder caused by a severe deficiency of thiamine that is most commonly observed in alcoholics. However, some have proposed that focal structural lesions disrupting memory circuits-in particular, the mammillary bodies, the mammillothalamic tract, and the anterior thalamus-can give rise to this amnestic syndrome. Here, the authors present 4 patients with reversible Korsakoff syndromes caused by suprasellar retrochiasmatic lesions compressing the mammillary bodies and adjacent caudal hypothalamic structures. Three of the patients were found to have large pituitary macroadenomas in their workup for memory deficiency and cognitive decline with minimal visual symptoms. These tumors extended superiorly into the suprasellar region in a retrochiasmatic position and caused significant mass effect in the bilateral mammillary bodies in the base of the brain. These 3 patients had complete and rapid resolution of amnestic problems shortly after initiation of treatment, consisting of resection in 1 case of nonfunctioning pituitary adenoma or cabergoline therapy in 2 cases of prolactinoma. The fourth patient presented with bizarre and hostile behavior along with significant memory deficits and was found to have a large cystic craniopharyngioma filling the third ventricle and compressing the midline diencephalic structures. This patient underwent cyst fenestration and tumor debulking, with a rapid improvement in his mental status. The rapid and dramatic memory improvement observed in all of these cases is probably due to a reduction in the pressure imposed by the lesions on structures contiguous to the third ventricle, rather than a direct destructive effect of the tumor, and highlights the essential role of the caudal diencephalic structures-mainly the mammillary bodies-in memory function. In summary, large pituitary lesions with suprasellar retrochiasmatic extension and third ventricular craniopharyngiomas can cause severe Korsakoff-like amnestic syndromes, probably because of bilateral pressure on or damage to mammillary bodies, anterior thalamic nuclei, or their major connections. Neuropsychiatric symptoms may rapidly and completely reverse shortly after initiation of therapy via surgical decompression of tumors or pharmacological treatment of prolactinomas. Early identification of these lesions with timely treatment can lead to a favorable prognosis for this severe neuropsychiatric disorder.

Ventriculoscopic Surgery for Cystic Retrochiasmatic Craniopharyngiomas: Indications, Surgical Technique, and Short-Term Patient Outcomes.

BACKGROUND: Attempted gross-total resection for the management of cystic retrochiasmatic craniopharyngiomas can cause severe hypothalamic dysfunction and decrease overall survival. Ventriculoscopic surgery is a minimally invasive alternative; however, potential indications and technique have not been well defined. OBJECTIVE: To present our indications and technique for the ventriculoscopic treatment of cystic retrochiasmatic craniopharyngiomas. METHODS: We evaluated all patients with retrochiasmatic craniopharyngiomas for ventriculoscopic surgery. Indications and operative technique were developed to minimize operative morbidity, relieve mass effect, and optimize functional outcome. Cyst size and functional outcomes were statistically evaluated to determine radiographic and short-term clinical outcome. RESULTS: Indications for ventriculoscopic surgery included (1) radiographic evidence of hypothalamic involvement and (2) major cystic component. Ten patients met indications, and mean follow-up was 2.5 ± 1.6 yr. The surgical technique included wide cyst fenestration at the foramen of Monro, and fenestration of inferior cyst wall/third ventriculostomy ("through-and-through" technique). Preoperative Karnofsky performance status was 70 ± 15 and was inversely correlated with preoperative cyst size (13 ± 13 cm3). A statistically significant reduction in cyst size was found on early postoperative imaging (2.1 ± 4.3 cm3). Seven patients received postoperative radiotherapy. Postoperative performance scores (81 ± 8.3) had improved; no patient suffered functional decline. Pre- and postoperative body mass indices were similar. No patient had short-term hypothalamic obesity. CONCLUSION: Ventriculoscopic surgery, with or without adjuvant treatments, can reduce early postoperative tumor volume and improve short-term functional status in cystic retrochiasmatic craniopharyngiomas with hypothalamic involvement; it should be considered a minimally invasive option in the multimodal treatment of craniopharyngiomas. Further studies are needed to determine long-term efficacy.

Criteria for the definition of Pituitary Tumor Centers of Excellence (PTCOE): A Pituitary Society Statement.

INTRODUCTION: With the goal of generate uniform criteria among centers dealing with pituitary tumors and to enhance patient care, the Pituitary Society decided to generate criteria for developing Pituitary Tumors Centers of Excellence (PTCOE). METHODS: To develop that task, a group of ten experts served as a Task Force and through two years of iterative work an initial draft was elaborated. This draft was discussed, modified and finally approved by the Board of Directors of the Pituitary Society. Such document was presented and debated at a specific session of the Congress of the Pituitary Society, Orlando 2017, and suggestions were incorporated. Finally the document was distributed to a large group of global experts that introduced further modifications with final endorsement. RESULTS: After five years of iterative work a document with the ideal criteria for a PTCOE is presented. CONCLUSIONS: Acknowledging that very few centers in the world, if any, likely fulfill the requirements here presented, the document may be a tool to guide improvements of care delivery to patients with pituitary disorders. All these criteria must be accommodated to the regulations and organization of Health of a given country.

"Micromegaly": an update on the prevalence of acromegaly with apparently normal GH secretion in the modern era.

PURPOSE: Approximately 25 % of cases of clinically active acromegaly cases treated in our academic center between 1996 and 2000, were diagnosed in patients who had elevated plasma IGF-1 levels, but apparently "normal" 24-h mean plasma GH levels. The current study served to update the data for patients with acromegaly referred to our facility, after increasing awareness of this "normal" GH subpopulation throughout the medical community. METHODS: A retrospective chart review was conducted on 157 patients with acromegaly who underwent resection of a confirmed somatotroph pituitary adenoma at the University of Michigan Health System between the dates of 1 Jan 2001 to 23 Sept 2015. RESULTS: Overall prevalence of acromegalic patients with "normal" GH levels, defined as GH <4.7 ng/mL, was 31 %. Over time, the percentage of patients with "normal" GH at diagnosis did not decline: 26 % from 2001 to 2005, 19 % from 2006 to 2010, and 47 % from 2011 to 2015. Mean pituitary tumor size was 1.8 ± 0.1 cm for the group with elevated GH, and 1.2 ± 0.1 cm for the group with "normal" GH (p < 0.001). Percent microadenomas was higher in a group with "normal" GH as compared to those with elevated GH (48 vs. 12 %, p < 0.001), and tumors >2 cm in the maximal diameter were encountered more frequently in the group with elevated GH (43 vs. 14 %, p < 0.001). CONCLUSIONS: Our data show that a substantial percentage of patients with clinical acromegaly have "normal" GH, and therefore strengthens the growing body of evidence which supports the leading role of IGF-1 levels in diagnostic evaluation. At the present time, questions about the natural course of "micromegaly" and treatment benefits compared to the subpopulation with elevated GH levels remain unanswered, but research continues to build on our understanding of the heterogeneous population of individuals.

The Role of Radiotherapy in Acromegaly.

Radiotherapy has, historically, played a central role in the management of acromegaly, and the last 30 years have seen substantial improvements in the technology used in the delivery of radiation therapy. More recently, the introduction of highly targeted radiotherapy, or 'radiosurgery', has further increased the therapeutic options available in the management of secretory pituitary tumors. Despite these developments, improvements in primary surgical outcomes, an increase in the range and effectiveness of medical therapy options, and long-term safety concerns have combined to dictate that, although still deployed in selected cases, the use of radiotherapy in the management of acromegaly has declined steadily over the past 2 decades. In this article, we review some of the main studies that have documented the efficacy of pituitary radiotherapy on growth hormone hypersecretion and summarize the data around its potential deleterious effects, including hypopituitarism, cranial nerve damage, and the development of radiation-related intracerebral tumors. We also give practical recommendations to guide its future use in patients with acromegaly, generally, as a third-line intervention after neurosurgical intervention in combination with various medical therapy options.

Outcome of Transsphenoidal Surgery for Cushing Disease: A Single-Center Experience Over 32 Years.

BACKGROUND: Transsphenoidal surgery is the standard approach for treating Cushing disease. Evidence is needed to document effectiveness. OBJECTIVE: To analyze results of transsphenoidal surgery in 276 consecutive patients, including 19 children. METHODS: Medical records were reviewed for patients treated initially with surgery for Cushing disease from 1980 to 2012. Radiographic features, pathology, remissions, recurrences, and complications were recorded. Patients were categorized for statistical analysis based on tumor size (microadenomas, macroadenomas, and negative imaging) and remission type (type 1 = morning cortisol ≤3 µg/dL; type 2 = morning cortisol normal). RESULTS: Females comprised 78% of patients and were older than men. Imaging showed 50% microadenomas, 13% macroadenomas, and 37% negative for tumor. Remission rates for microadenomas, macroadenomas, and negative imaging were 89%, 66%, and 71%, respectively. Patients with microadenomas were more likely to have type 1 remission. Pathology showed adrenocorticotropic hormone-secreting adenomas in 82% of microadenomas, in 100% of macroadenomas, and in 43% of negative imaging. The incidence of hyperplasia was 8%. The finding of hyperplasia or no tumor on pathology predicted treatment failure. The recurrence rate was 17%, with an average time to recurrence of 4.0 years. Patients with type 1 remission had a lower rate of recurrence (13% type 1 vs 50% type 2) and a longer time to recurrence. Children had similar imaging findings, remission rates, and pathology. There were no operative deaths. CONCLUSION: Transsphenoidal surgery provides a safe and effective treatment for Cushing disease. For both adults and children, the best outcomes occurred in patients with microadenomas and/or those with type 1 remission.

The care continuum in acromegaly: how patients, nurses, and physicians can collaborate for successful treatment experiences.

Patients with acromegaly (a condition of chronic growth hormone hypersecretion by a pituitary adenoma) often require pharmacological treatment. Somatostatin analogs (SSAs) such as pasireotide, lanreotide, and octreotide are frequently used as first-line medical therapy. As SSAs are delivered by regular subcutaneous or intramuscular injections, they can result in injection-related pain or anxiety and can be challenging to fit into patients' lifestyles. When combined with the prolonged, debilitating psychological complications associated with acromegaly, these administration challenges can negatively impact compliance, adherence, and quality of life. Proactively managing patients' expectations and providing appropriate, timely guidance are crucial for maximizing adherence, and ultimately, optimizing the treatment experience. As part of ongoing clinical research since 1997, our team at the University of Michigan has used SSAs to treat 30 patients with acromegaly. Based on our clinical experiences with multiple SSA administration regimens (long-acting intramuscular, long-acting deep subcutaneous, and twice-daily subcutaneous), we generated a dialog map that guides health care professionals through the many sensitive and complex patient communication issues surrounding this treatment process. Beginning with diagnosis, the dialog map includes discussion of treatment options, instruction on proper drug administration technique, and ensuring of appropriate follow-up care. At each step, we provide talking points that address the following: the patients' clinical situation; their geographic, economic, and psychological concerns; and their inclination to communicate with clinicians. We have found that involving patients, nurses, and physicians as equal partners in the treatment process optimizes treatment initiation, adherence, and persistence in acromegaly. By encouraging collaboration across the care continuum, this dialog map can facilitate identification of the treatment plan that is most likely to yield the best possible outcome.

Gene expression changes in subcutaneous adipose tissue due to Cushing's disease.

Glucocorticoids have major effects on adipose tissue metabolism. To study tissue mRNA expression changes induced by chronic elevated endogenous glucocorticoids, we performed RNA sequencing on the subcutaneous adipose tissue from patients with Cushing's disease (n=5) compared to patients with nonfunctioning pituitary adenomas (n=11). We found a higher expression of transcripts involved in several metabolic pathways, including lipogenesis, proteolysis and glucose oxidation as well as a decreased expression of transcripts involved in inflammation and protein synthesis. To further study this in a model system, we subjected mice to dexamethasone treatment for 12 weeks and analyzed their inguinal (subcutaneous) fat pads, which led to similar findings. Additionally, mice treated with dexamethasone showed drastic decreases in lean body mass as well as increased fat mass, further supporting the human transcriptomic data. These data provide insight to transcriptional changes that may be responsible for the comorbidities associated with chronic elevations of glucocorticoids.

Gene Expression Signature in Adipose Tissue of Acromegaly Patients.

To study the effect of chronic excess growth hormone on adipose tissue, we performed RNA sequencing in adipose tissue biopsies from patients with acromegaly (n = 7) or non-functioning pituitary adenomas (n = 11). The patients underwent clinical and metabolic profiling including assessment of HOMA-IR. Explants of adipose tissue were assayed ex vivo for lipolysis and ceramide levels. Patients with acromegaly had higher glucose, higher insulin levels and higher HOMA-IR score. We observed several previously reported transcriptional changes (IGF1, IGFBP3, CISH, SOCS2) that are known to be induced by GH/IGF-1 in liver but are also induced in adipose tissue. We also identified several novel transcriptional changes, some of which may be important for GH/IGF responses (PTPN3 and PTPN4) and the effects of acromegaly on growth and proliferation. Several differentially expressed transcripts may be important in GH/IGF-1-induced metabolic changes. Specifically, induction of LPL, ABHD5, and NRIP1 can contribute to enhanced lipolysis and may explain the elevated adipose tissue lipolysis in acromegalic patients. Higher expression of TCF7L2 and the fatty acid desaturases FADS1, FADS2 and SCD could contribute to insulin resistance. Ceramides were not different between the two groups. In summary, we have identified the acromegaly gene expression signature in human adipose tissue. The significance of altered expression of specific transcripts will enhance our understanding of the metabolic and proliferative changes associated with acromegaly.

Rapid development of systemic insulin resistance with overeating is not accompanied by robust changes in skeletal muscle glucose and lipid metabolism.

Prolonged overeating and the resultant weight gain are clearly linked with the development of insulin resistance and other cardiometabolic abnormalities, but adaptations that occur after relatively short periods of overeating are not completely understood. The purpose of this study was to characterize metabolic adaptations that may accompany the development of insulin resistance after 2 weeks of overeating. Healthy, nonobese subjects (n = 9) were admitted to the hospital for 2 weeks, during which time they ate ∼4000 kcals·day(-1) (70 kcal·kg(-1) fat free mass·day(-1)). Insulin sensitivity was estimated during a meal tolerance test, and a muscle biopsy was obtained to assess muscle lipid accumulation and protein markers associated with insulin resistance, inflammation, and the regulation of lipid metabolism. Whole-body insulin sensitivity declined markedly after 2 weeks of overeating (Matsuda composite index: 8.3 ± 1.3 vs. 4.6 ± 0.7, p < 0.05). However, muscle markers of insulin resistance and inflammation (i.e., phosphorylation of IRS-1-Ser(312), Akt-Ser(473), and c-Jun N-terminal kinase) were not altered by overeating. Intramyocellular lipids tended to increase after 2 weeks of overeating (triacylglyceride: 7.6 ± 1.6 vs. 10.0 ± 1.8 nmol·mg(-1) wet weight; diacylglyceride: 104 ± 10 vs. 142 ± 23 pmol·mg(-1) wet weight) but these changes did not reach statistical significance. Overeating induced a 2-fold increase in 24-h insulin response (area under the curve (AUC); p < 0.05), with a resultant ∼35% reduction in 24-h plasma fatty acid AUC (p < 0.05). This chronic reduction in circulating fatty acids may help explain the lack of a robust increase in muscle lipid accumulation. In summary, our findings suggest alterations in skeletal muscle metabolism may not contribute meaningfully to the marked whole-body insulin resistance observed after 2 weeks of overeating.

Complex rhythmicity and age dependence of growth hormone secretion are preserved in patients with acromegaly: further evidence for a present hypothalamic control of pituitary somatotropinomas.

CONTEXT: Traditionally, acromegaly is viewed as a disease resulting from GH hypersecretion from an autonomous pituitary somatotropinoma. OBJECTIVE: To test the hypothesis that GH secretion in acromegaly is still subjected to normal hypothalamic control, we studied the daily rhythmicity of GH secretion in normal controls and patients with newly diagnosed, untreated acromegaly. DESIGN AND SETTING: This was an observational inpatient study in the General Clinical Research Center at the University of Michigan. PATIENTS OR OTHER PARTICIPANTS: One hundred four normal controls and 67 acromegalic patients were included in the study. INTERVENTION: The intervention consisted of frequent blood sampling over 24 hours. MAIN OUTCOME MEASURE(S): We hypothesized that acromegalic patients would show rhythmicity, sexual dimorphism, and age-related decline of GH secretion similar to normal controls. RESULTS: Both normal controls and the patients exhibited 3 major GH waves with the highest values at 12:00 pm, 5:00 pm, and 1:00 am (P < .001 for all). Both controls and patients exhibited a clear appearance of the nocturnal GH waves, irrespective of the gender (P < .001 for all). The amplitude of the maximal (nocturnal) GH secretory wave (1:00 am) as compared with the nadir GH secretion (9:00 am) was clearly different between the 2 groups, with a significantly smaller magnitude in acromegaly (P < .001). A subsequent subanalysis of both groups was performed separately for both genders. Similar to the entire groups, both controls and patients exhibited a clear appearance of the nocturnal GH waves, irrespective of the gender (P < .001 for all). Patients with clearly elevated GH values have shown an age-related decline of GH secretion (r = -0.35, P < .001), similar to controls. CONCLUSIONS: The analysis of GH profiles in multiple patients with untreated acromegaly discloses the persistence of the hallmarks of the central control of GH regulation, ie, nictohemeral rhythmicity, sexual dimorphism, and an age-related decline of GH output.

Repeat endoscopic transsphenoidal surgery for acromegaly: remission and complications.

Reported biochemical remission rates following surgical intervention for acromegaly range from 38 to 83%. In patients not achieving surgical remission, few options remain, mostly limited to medical management and radiation therapy. There is debate over whether or not to offer reoperation to patients in whom surgical remission is not achieved with initial resection. Retrospective chart review was undertaken to determine all patients having acromegaly with persistently elevated GH and/or IGF-1 levels after initial pituitary adenoma resection, and who underwent reoperation using endoscopic endonasal approach at a single institution. Biochemical remission was defined as a postoperative GH level <1 ng/mL and a normal postoperative IGF-1 level in the absence of any medical therapy. In total, 14 patients underwent repeat surgical intervention for acromegaly via endoscopic transsphenoidal approach. Of the 14 patients, 8 (57%) achieved biochemical remission following repeat surgical intervention. Lower preoperative GH levels were associated with greater chance of biochemical remission (P = 0.048). New endocrinopathies were seen in 2 patients (14%), and both were transient diabetes insipidus. Meningitis occurred in 2 patients (14%); both were aseptic meningitis with no sequelae. No mortality was encountered. Repeat surgical intervention for acromegaly via endoscopic transsphenoidal approach appears safe and effective. With no mortality and minimal morbidity, repeat surgical intervention via endoscopic transsphenoidal approach appears a reasonable option for these hard-to-treat patients and should be considered for patients in whom surgical remission is not achieved with initial surgery.

Suppression in growth hormone during overeating ameliorates the increase in insulin resistance and cardiovascular disease risk.

Previously, we reported that overeating for only a few days markedly suppressed the secretion of growth hormone (GH). The purpose of the present study was to determine the role of this reduction in GH concentration on key metabolic adaptations that occur during 2 wk of overeating. Nine nonobese, healthy adults were admitted to the hospital for 2 wk, during which time they ate ∼4,000 kcal/day (70 kcal·kg fat-free mass(-1)·day(-1); 50% carbohydrate, 35% fat, and 15% protein), and their plasma GH concentration was allowed to decline naturally (control). An additional eight subjects underwent the same overeating intervention and received exogenous GH treatment (GHT) administered in four daily injections to mimic physiological GH secretion throughout the 2-wk overeating period. We measured plasma insulin and glucose concentrations in the fasting and postprandial state as well as fasting lipolytic rate, proteolytic rate, and fractional synthetic rate (FSR) using stable-isotope tracer methods. GHT prevented the fall in plasma GH concentration, maintaining plasma GH concentration at baseline levels (1.2 ± 0.2 ng/ml), which increased fasting and postprandial assessments of insulin resistance (P < 0.05) and increased fasting lipidemia (all P < 0.05 vs. control). In addition, preventing the suppression in GH with overeating also blunted the increase in systemic proteolysis (P < 0.05 GHT vs. control). However, GHT did not alter lipolysis or FSR in response to overeating. In conclusion, our main findings suggest that the suppression in GH secretion that naturally occurs during the early stages of overeating may help attenuate the insulin resistance and hyperlipidemia that typically accompany overeating.

Clinical problem solving: monster on the hook--case problems in neurosurgery.

BACKGROUND AND OBJECTIVE: Nonfunctioning and functioning pituitary tumors can present in numerous ways. They may be difficult to diagnose correctly and, even with proper treatment, may lead to complications. METHODS: We present the case of a patient who presented with a large, invasive sellar mass and underwent both medical and surgical treatment for this lesion. The patient's course did not progress as was expected from his initial workup. RESULTS: The patient's history, physical examination, laboratory values, pathologic specimens, and radiologic findings are discussed. His management before, during, and after medical therapy and surgery is reviewed by pituitary experts from 2 different institutions. Aspects of diagnosis and management of sellar lesions are presented and reviewed in the literature. CONCLUSION: Neurosurgeons frequently treat patients with sellar lesions and should remember that despite modern laboratory, pathologic, and radiologic techniques, the diagnosis and treatment of these lesions is not always clear.

Rapid suppression of growth hormone concentration by overeating: potential mediation by hyperinsulinemia.

CONTEXT: The very low GH concentration in obesity is commonly attributed to high body fat mass; however, the influence of overeating on GH secretion is not clear. OBJECTIVE: The aim of the study was to examine the effects of 2 wk of overeating on changes in GH secretion. SETTING: Subjects were admitted to the hospital and stayed within the Michigan Clinical Research Unit throughout the entire 2-wk overeating period. PARTICIPANTS: We studied seven healthy, nonobese men (body mass index, 24 ± 1 kg/m(2); age, 25 ± 1 yr). INTERVENTION: Subjects ate standardized meals containing 70 kcal/kg fat free mass/d (∼4000 kcal/d) for 2 wk. MAIN OUTCOME MEASURES: Twenty-four-hour plasma concentrations of GH (every 20 min) and insulin (every 2 h) were measured before overeating (baseline), on d 3, and after 2 wk of overeating. RESULTS: Compared with baseline, average 24-h plasma GH concentration declined nearly 80% by d 3 of overeating (1.30 ± 0.18 vs. 0.36 ± 0.09 ng/ml; P = 0.01). This marked suppression of GH secretion occurred in the absence of an increase in body weight (77.0 ± 2.2 vs. 76.4 ± 2.4 kg). At the same time, average 24-h insulin concentration doubled (16.6 ± 2.1 vs. 31.7 ± 5.8 µU/ml; P = 0.009). After 2 wk, body weight significantly increased (79.0 ± 2.1 kg; P < 0.001), and body fat increased by more than 10% (P = 0.002). However, this did not induce a further suppression in plasma GH concentration (0.33 ± 0.08 ng/ml). CONCLUSION: Only a few days of overeating markedly suppressed GH secretion before any measurable weight gain and was accompanied by chronic hyperinsulinemia. Increased body weight and body fat by 2 wk of overeating did not further suppress GH secretion.

Current diagnosis of acromegaly.

Acromegaly is a rare and chronic condition that is characterized by sustained unregulated hypersecretion of growth hormone (GH). More than 99% of the cases of acromegaly are due to a pathologic proliferation of pituitary somatotrophs presenting in the form of a pituitary adenoma. The excessive amounts of GH and its target hormone, insulin like growth factor-1 (IGF-1) cause metabolic changes and tissue enlargement that, collectively, lead to significant morbidity and a two to threefold increase in mortality. Thus, early diagnosis has proved to be crucial to improve survival and quality of life in this condition. The development of radioimmunoassay (RIA) in the 1960s provided clinicians with a biochemical tool to diagnose acromegaly. Many limitations were inherent to this methodology which necessitated the development of more sensitive tools, such as immunoradiometric (IRMA) or immunoluminometric (ILMA) assays for GH and IGF-1 measurements. These newer assays have not come without imperfections. The reference ranges to describe normalcy of the somatotropic axis and the biochemical criteria of "cure" of acromegaly are areas of great debate. Nevertheless, the current international consensus agrees that the diagnosis of acromegaly should be based on both clinical presentation and biochemical data.

Treatment of pituitary tumors: a surgical perspective.

Surgical intervention is a necessary part of a multimodal approach to pituitary lesions. This article summarizes the surgical approach to different neoplastic processes affecting the sellar region.