Outcomes of stereotactic radiosurgery and hypofractionated stereotactic radiotherapy for refractory Cushing's disease.

PURPOSE: Hypofractionated stereotactic radiotherapy (HSRT) for refractory Cushing's disease may offer a condensed treatment schedule for patients with large tumors abutting the optic chiasm unsuitable for stereotactic radiosurgery (SRS). To-date only four patients have been treated by HSRT in the published literature. We investigated the feasibility, toxicity, and efficacy of HSRT compared to SRS. METHODS: After approval, we retrospectively evaluated patients treated at our institution for refractory Cushing's disease with SRS or HSRT. Study outcomes included biochemical control, time to biochemical control, local control, and late complications. Binary logistic regression and Cox proportional hazards regression evaluated predictors of outcomes. RESULTS: Patients treated with SRS (n = 9) and HSRT (n = 9) were enrolled with median follow-up of 3.4 years. Clinicopathologic details were balanced between the cohorts. Local control was 100% in both cohorts. Time to biochemical control was 6.6. and 9.5 months in the SRS and HSRT cohorts, respectively (p = 0.6258). Two patients in each cohort required salvage bilateral adrenalectomy. Late complications including secondary malignancy, radionecrosis, cranial nerve neuropathy, and optic pathway injury were minimal for either cohort. CONCLUSIONS: HSRT is an appropriate treatment approach for refractory Cushing's disease, particularly for patients with large tumors abutting the optic apparatus. Prospective studies are needed to validate these findings and identify factors suggesting optimal fractionation approaches.

Effects of gender, body weight, and blood glucose dynamics on the growth hormone response to the glucagon stimulation test in patients with pituitary disease.

OBJECTIVE: Body weight blunts the growth hormone (GH) response to provocative stimuli. The appropriate GH cut-off to confirm GH deficiency in obese and overweight patients undergoing the glucagon stimulation test (GST) has recently been questioned. We hypothesized that the peak GH would be inversely related to the nadir blood glucose (BG) after glucagon and that this may be a mechanism influencing peak GH in overweight patients. This retrospective study examined effects of gender, body weight, and BG dynamics on GH response to GST in patients evaluated in our Pituitary Center. DESIGN: Adult patients who underwent GST from September 2009-2014 were included. Continuous variable comparisons were analyzed using the Mann-Whitney U-test and categorical data by Fisher's Exact Test. Spearman correlation was used to determine associations between continuous variables. RESULTS: 42 patients (N=28, 66.7% female) had sufficient data for analysis. Obese patients (N=26) had a reduced GH response, summarized as GH area under the curve (AUC) (p=0.03 vs. non-obese patients) and higher BG during GST, summarized as AUC (p<0.01 vs. non-obese patients). Obese women (N=19), in particular, stimulated lower (p=0.03 vs. non-obese women) and had a higher nadir BG (p=0.03 vs. non-obese women). While weight correlated with extent (rs=0.35; p=0.02) and timing (rs=0.31; p=0.05) of nadir BG reached, there was no significant correlation between BG dynamics and the GH response in the total population (N=42). Ten patients (7 with pan anterior hypopituitarism, defined as 3 anterior pituitary deficiencies) had a peak GH≤0.1ng/mL during GST. When these subjects with a negligible peak GH response were excluded from the analysis, weight was associated with GH AUC (rs=-0.45; p=0.01), peak GH response (rs=-0.42; p=0.02) and nadir BG (rs=0.48; p<0.01). Furthermore, the nadir BG achieved during GST was inversely related to GH AUC (rs=-0.38; p=0.03) and peak GH (rs=-0.37; p=0.04) such that patients (N=32) with higher nadir BG had lower peak GH in response to glucagon. CONCLUSIONS: Obese patients, particularly women, do not respond as robustly to glucagon stimulation. These data suggest that there exists an altered BG profile during GST in obese individuals, and that a less robust hypoglycemic stimulus may contribute to an impaired GH response. We suggest measuring BG levels during glucagon stimulation testing to assist with clinical interpretation of GH dynamics. The diagnostic accuracy of the GST in patients with known disorders in glucose metabolism and those taking anti-diabetic medications deserves further study.

Imaging of Resected Nonfunctioning Pituitary Adenomas: The Cost of Surveillance.

Objectives To determine the cost of annual magnetic resonance imaging (MRI) surveillance after resection of nonfunctioning pituitary adenomas (NFPAs) and its effectiveness in reducing visual compromise due to tumor recurrence. Design Retrospective case series. Setting Vanderbilt University Medical Center (2003-2011). Participants A total of 120 patients underwent primary transsphenoidal resection and surveillance of NFPAs between 2003 and 2011. Main Outcome Measures Time from initial surgery to most recent imaging or progression. Surveillance MRI costs according to Centers for Medicare and Medicaid database and visual field deficits. Results Patients received 382 surveillance scans at a total cost of $218,477.30. The median follow-up was 47 months (interquartile range [IQR]: 26-76), and the median interval between scans was 357 days (IQR: 225-434). Overall, 50 scans (13%) revealed tumor growth. The cost per scan revealing growth was $4,369.55. The cost to identify 19 patients (16%) with clinically significant growth was $11,498.80 per patient. A total of 5 of 19 patients (26%) experienced new visual deficits prior to intervention. Patients with visual decline tended to have longer scan intervals than those with preserved vision (mean: 239 versus 794 days; p = 0.0584). No patient with annual surveillance imaging experienced visual decline. Conclusions Annual MRI scans are a sensitive and cost-conscious method to identify NFPA recurrence prior to visual decline.

Effects of GH in women with abdominal adiposity: a 6-month randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Abdominal adiposity is associated with increased cardiovascular risk and decreased GH secretion. The objective of our study was to determine the effects of GH on body composition and cardiovascular risk markers in abdominally obese women. MATERIALS AND METHODS: In this randomized, double-blind, placebo-controlled study, 79 obese premenopausal women received GH vs placebo for 6 months. Primary endpoints were i) total abdominal (total abdominal adipose tissue, TAT) fat by computed tomography (CT) (body composition) and ii) high-sensitivity C-reactive protein (hsCRP) (cardiovascular risk marker). Body composition was assessed by CT, dual-energy X-ray absorptiometry, and proton MR spectroscopy. Serum cardiovascular risk markers, carotid intima-media thickness, and endothelial function were measured. RESULTS: Mean 6-month GH dose was 1.7±0.1 mg/day, resulting in a mean IGF1 SDS increase from -1.7±0.08 to -0.1±0.3 in the GH group. GH administration decreased TAT and hsCRP compared with placebo. In addition, it increased thigh muscle mass and lean body mass and decreased subcutaneous abdominal and trunk fat, tissue plasminogen activator, apoB, and apoB/low-density lipoprotein compared with placebo. Visceral adipose tissue (VAT) decreased and intramyocellular lipid increased within the GH group. Six-month change in IGF1 levels was negatively associated with 6-month decrease in TAT and VAT. One subject had a 2 h glucose >200 mg/ml at 3 months; four subjects, three of whom were randomized to GH, had 2 h glucose levels >200 mg/ml at the end of the study. CONCLUSION: GH administration in abdominally obese premenopausal women exerts beneficial effects on body composition and cardiovascular risk markers but is associated with a decrease in glucose tolerance in a minority of women.

Safety and cost effectiveness of early discharge following microscopic trans-sphenoidal resection of pituitary lesions.

BACKGROUND: Inpatient hospitalization following trans-sphenoidal resection of a pituitary neoplasm has traditionally involved a hospital stay of 2 days or more. It has been the policy of the senior pituitary neurosurgeon (GSA) since February 2008 to allow discharge home on postoperative day (POD) 1 if thirst mechanism is intact and the patient is tolerating oral hydration. The goal of this study was to evaluate the safety and cost-effectiveness of this practice. METHODS: We reviewed the charts of 30 patients, designated the early discharge group, who consecutively underwent microscopic trans-sphenoidal resection from February 2008 to December 2009. We then reviewed the charts of 30 patients, designated the standard discharge group, who consecutively underwent trans-sphenoidal resection from May 2007 to February 2008 before discharge home on POD1 was considered an appropriate option. Safety and cost-effectiveness of the two patient groups were retrospectively evaluated. RESULTS: Patients in the early discharge group went home, on average, on POD 1.3. Following exclusion of two outliers, the average date of discharge of patients in the standard discharge group was POD 2.2. The policy of early discharge saved an average of $1,949 per patient-approximately 4% the total cost of the procedure. Trends toward decreased costs did not reach statistical significance. While no patient suffered any measurable morbidity as a result of early discharge home, 1 in 3 patients in the early discharge group required unscheduled postoperative re-evaluation-a figure significantly higher than the standard discharge group. CONCLUSIONS: At a dedicated pituitary center with the resources to closely monitor outpatient endocrinological and postsurgical issues, early discharge home following trans-sphenoidal surgery is a safe option that is associated with an increase in the number of unscheduled postoperative visits and a trend toward lower costs.

Growth hormone deficiency is associated with decreased quality of life in patients with prior acromegaly.

CONTEXT: Both GH deficiency (GHD) and GH excess are associated with a decreased quality of life. However, it is unknown whether patients with GHD after treatment for acromegaly have a poorer quality of life than those with normal GH levels after cure of acromegaly. OBJECTIVE: The aim of the study was to determine whether patients with GHD and prior acromegaly have a poorer quality of life than those with GH sufficiency after cure of acromegaly. DESIGN AND SETTING: We conducted a cross-sectional study in a General Clinical Research Center. STUDY PARTICIPANTS: Forty-five patients with prior acromegaly participated: 26 with GHD and 19 with GH sufficiency. INTERVENTION: There were no interventions. MAIN OUTCOME MEASURES: We evaluated quality of life, as measured by 1) the Quality of Life Adult Growth Hormone Deficiency Assessment (QoL-AGHDA); 2) the Short-Form Health Survey (SF-36); and 3) the Symptom Questionnaire. RESULTS: Mean scores on all subscales of all questionnaires, except for the anger/hostility and anxiety subscales of the Symptom Questionnaire, showed significantly impaired quality of life in the GH-deficient group compared with the GH-sufficient group. Peak GH levels after GHRH-arginine stimulation levels were inversely associated with QoL-AGHDA scale scores (R = -0.53; P = 0.0005) and the Symptom Questionnaire Depression subscale scores (R = -0.35; P = 0.031) and positively associated with most SF-36 subscale scores. CONCLUSIONS: Our data are the first to demonstrate a reduced quality of life in patients who develop GHD after cure of acromegaly compared to those who are GH sufficient. Further studies are warranted to determine whether GH replacement would improve quality of life for patients with GHD after cure from acromegaly.

Anthropometry, CT, and DXA as predictors of GH deficiency in premenopausal women: ROC curve analysis.

Visceral adiposity is a strong determinant of growth hormone (GH) secretion, and states of GH deficiency are associated with increased visceral adiposity and decreased lean body mass. The purpose of our study was to determine the sensitivity and specificity of different methods of assessing body composition [anthropometry, dual-energy X-ray absorptiometry (DXA), and computed tomography (CT)] to predict GH deficiency in premenopausal women and threshold values for each technique to predict GH deficiency, using receiver operator characteristic (ROC) curve analysis. We studied a group of 45 healthy lean, overweight, and obese premenopausal women who underwent anthropometric measurements (body mass index, waist and hip circumferences, skin fold thickness), DXA, CT, and a GH-releasing hormone-arginine stimulation test. ROC curve analysis was used to determine cutoff values for each method to identify GH deficiency. Visceral adiposity measured by CT showed the highest sensitivity and specificity for identifying subjects with GH deficiency with a cutoff of >9,962 mm(2) [area under the curve (AUC), 0.95; sensitivity, 100%; specificity, 77.8%; P = 0.0001]. Largest waist circumference showed high sensitivity and specificity with a cutoff of >101.7 cm (AUC, 0.89; sensitivity, 88.9%; specificity, 75%; P = 0.0001). When the ROC curves of visceral fat measured by CT and largest waist circumference were compared, the difference between the two methods was not statistically significant (P = 0.36). Our study showed that the largest waist circumference predicts the presence of GH deficiency in healthy premenopausal women with high sensitivity and specificity and nearly as well as CT measurement of visceral adiposity. It can be used to identify women in whom GH deficiency is likely and therefore in whom formal GH stimulation testing might be indicated.

Growth hormone deficiency by growth hormone releasing hormone-arginine testing criteria predicts increased cardiovascular risk markers in normal young overweight and obese women.

CONTEXT: Little is known about the relationship between GH and cardiovascular risk markers in women without organic hypothalamic/pituitary disease. OBJECTIVE: The objective of the study was to determine whether healthy young overweight and obese women, who would be classified as having GH deficiency (GHD) based on standard criteria used in hypopituitarism (peak GH after stimulation with GHRH and arginine < 5 ng/ml), have increased cardiovascular risk markers. DESIGN: This was a cross-sectional study. SETTING: The study was conducted at the General Clinical Research Center. STUDY PARTICIPANTS: Forty-five women of reproductive age, mean age 33.1 +/- 1.2 yr and mean body mass index (BMI) 30.9 +/- 1.0 kg/m(2). INTERVENTION: There was no intervention. MAIN OUTCOME MEASURES: Measures included carotid intima-medial thickness, high-sensitivity C-reactive protein (hsCRP), total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein, triglycerides, E-selectin, soluble intercellular adhesion molecule-1, TNF-alpha receptor I, TNF-alpha receptor II, fasting insulin levels, and oral glucose tolerance testing. RESULTS: Twenty-six percent of overweight or obese subjects and none with BMI less than 25 kg/m(2) met criteria for GHD. Subjects who met GHD criteria had a mean BMI of 37.0 +/- 1.7 kg/m(2) (range 28.6-43.6 kg/m(2)), and their mean waist circumference (110.1 +/- 3.5 cm) was higher than in overweight/obese women with GH sufficiency (P = 0.007). Mean carotid intima-media thickness, hsCRP, soluble intercellular adhesion molecule-1, TNF-alpha receptor I, and TNF-alpha receptor II levels were higher, and HDL lower, in women meeting GHD criteria than in GH sufficiency. Differences in HDL, hsCRP, and TNF-alpha receptor II remained after controlling for age plus BMI, waist circumference, or trunk fat. There were no differences in measures of insulin resistance. CONCLUSIONS: There may be a relative GHD syndrome in overweight and obese women without organic pituitary or hypothalamic disease that confers increased cardiovascular risk, independent of weight.

Peptide YY (PYY) levels and bone mineral density (BMD) in women with anorexia nervosa.

INTRODUCTION: Anorexia nervosa (AN) is a psychiatric illness that results in significant bone loss. Studies examining the neuroendocrine dysregulation that occurs in AN may increase understanding of endocrine systems that regulate bone mass. Peptide YY (PYY) is an anorexigenic peptide derived primarily from the intestine, with actions mediated via activation of Y receptors. We have previously shown that PYY levels are elevated in adolescents with AN. Y2 receptor knockout mice have increased bone mineral density (BMD) and thus PYY may play a role in regulating bone mass. We hypothesized that PYY levels would be inversely associated with BMD in women with AN. METHODS: This was a cross-sectional study performed in a General Clinical Research Center of 12 adult women with AN, (mean+/-SEM) mean age 30.9+/-1.8 years, BMI 17.1+/-0.4 kg/m2, and % ideal body weight 77.5+/-1.7%. PYY concentrations were measured hourly from 20:00 h to 08:00 h. BMD was measured using dual X-ray absorptiometry (DXA). RESULTS: In women with AN, mean overnight PYY levels strongly inversely correlated with BMD at the PA spine (r=-0.77, p=0.003), lateral spine (r=-0.82, p=0.002), total hip (r=-0.75, p=0.005), femoral neck (r=-0.72, p=0.009), total radius (r=-0.72, p=0.009) and 1/3 distal radius (r=-0.81, p=0.002). Body mass index was inversely correlated with PYY level (r=-0.64, p=0.03). Multivariate stepwise regression analysis was performed to determine the contribution of age, duration of AN, BMI, fat-free mass, and PYY to BMD. For PA and lateral spine, PYY was the primary determinant of BMD, accounting for 59% and 67% of the variability, respectively. Fat-free mass and duration of anorexia nervosa were the primary determinants of BMD at other skeletal sites. CONCLUSIONS: In women with anorexia nervosa, an elevated PYY level is strongly associated with diminished BMD, particularly at the spine. Therefore further investigation of the hypothesis that PYY may contribute to the prevalent bone pathology in this disorder is merited.

Growth hormone decreases visceral fat and improves cardiovascular risk markers in women with hypopituitarism: a randomized, placebo-controlled study.

CONTEXT: Data regarding gender-specific efficacy of GH on critical endpoints are lacking. There are no randomized, placebo-controlled studies of physiological GH therapy solely in women. OBJECTIVE: Our objective was to determine the effects of physiological GH replacement on cardiovascular risk markers and body composition in women with GH deficiency (GHD). DESIGN: This was a 6-month, randomized, placebo-controlled, double-blind study. SETTING: The study was conducted at the General Clinical Research Center. STUDY PARTICIPANTS: 43 women with GHD due to hypopituitarism were included in the study. INTERVENTION: Study participants were randomized to receive GH (goal mid-normal serum IGF-1) or placebo. MAIN OUTCOME MEASURES: Cardiovascular risk markers, including high-sensitivity C-reactive protein, tissue plasminogen activator, and body composition, including visceral adipose tissue by cross-sectional computed tomography, were measured. RESULTS: Mean daily GH dose was 0.67 mg. The mean IGF-1 sd score increased from -2.5 +/- 0.3 to -1.4 +/- 0.9 (GH) (P < 0.0001 vs. placebo). High-sensitivity C-reactive protein decreased by 38.2 +/- 9.6% (GH) vs.18.2 +/- 6.0% (placebo) (P = 0.03). Tissue plasminogen activator and total cholesterol decreased, and high-density lipoprotein increased. Homeostasis model assessment-insulin resistance and other markers were unchanged. Body fat decreased [-5.1 +/- 2.0 (GH) vs. 1.9 +/- 1.0% (placebo); P = 0.002] as did visceral adipose tissue [-9.0 +/- 5.9 (GH) vs. 4.3 +/- 2.7% (placebo); P = 0.03]. Change in IGF-1 level was inversely associated with percent change in visceral adipose tissue (r = -0.61; P = 0.002), total body fat (r = -0.69; P < 0.0001), and high-sensitivity C-reactive protein (r = -0.51; P = 0.003). CONCLUSIONS: Low-dose GH replacement in women with GHD decreased total and visceral adipose tissue and improved cardiovascular markers, with a relatively modest increase in IGF-1 levels and without worsening insulin resistance.

Pituitary surgery and postoperative management in Cushing's disease.

Transsphenoidal pituitary surgery is the therapy for most Cushing's disease patients. This article describes the surgical technique, efficacy, perioperative management, and complications associated with this procedure. Numerous biochemical tests of cortisol status have been studied for the evaluation of the postoperative patient. Factors that predict postoperative remission and future relapse of Cushing's disease are addressed. Secondary interventions for persistent or recurrent disease include repeat transsphenoidal resection, pituitary radiation, medical therapy, and bilateral adrenalectomy