Quality of life after long-term biochemical control of acromegaly.

PURPOSE: To assess long-term quality of life (QoL) in patients with sustained biochemical control of acromegaly, comparing those receiving vs not receiving pharmacotherapy (primary analysis); to assess change in QoL over time (secondary analysis). METHODS: Cross-sectional study, with a secondary longitudinal component, of 58 patients with biochemically controlled acromegaly. All had participated in studies assessing QoL years previously, after having undergone surgery ± radiotherapy. One cohort received medical therapy [MED (n = 33)]; the other did not [NO-MED (n = 25)]. QoL was assessed by the 36-Item-Short-Form Health Survey (SF-36), Acromegaly Quality of Life Questionnaire (AcroQoL), Gastrointestinal Quality of Life Index (GIQLI), Symptom Questionnaire, and QoL-Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA). RESULTS: Mean (± SD) duration of biochemical control was 15.0 ± 6.4 years for MED and 20.4 ± 8.2 years for NO-MED (p = 0.007). 58% of subjects scored < 25% of normal on ≥ 1 SF-36 domain and 32% scored < 25% of normal on ≥ 4 of 8 domains. Comparing MED vs NO-MED and controlling for duration of biochemical control, there were no significant differences in QoL by SF-36, AcroQOL, GIQLI, Symptom Questionnaire, or QoL-AGHDA. Growth hormone deficiency (GHD) but not radiotherapy predicted poorer QoL. In MED, QoL improved over time in three AcroQoL domains and two GIQLI domains. In NO-MED, QoL worsened in two SF-36 domains and two Symptom Questionnaire domains; QoL-AGHDA scores also worsened in subjects with GHD. CONCLUSION: A history of acromegaly and development of GHD, but not pharmacologic or radiotherapy, are detrimental to QoL, which remains poor over the long-term despite biochemical control.

Effects of growth hormone receptor antagonism and somatostatin analog administration on quality of life in acromegaly.

OBJECTIVE: Acromegaly is associated with impaired quality of life (QoL). We investigated the effects of biochemical control of acromegaly by growth hormone receptor antagonism vs somatostatin analog therapy on QoL. DESIGN: Cross-sectional. PATIENTS: 116 subjects: n = 55 receiving a somatostatin analog (SSA group); n = 29 receiving pegvisomant (PEG group); n = 32 active acromegaly on no medical therapy (ACTIVE group). MEASUREMENTS: Acromegaly QoL Questionnaire (AcroQoL), Rand 36-Item Short Form Survey (SF-36) and Gastrointestinal QoL Index (GIQLI); fasting glucose, insulin and IGF-1 levels (LC/MS, Quest Diagnostics). RESULTS: There were no group differences in mean age, BMI or sex [(whole cohort mean ± SD) age 52 ± 14 years, BMI 30 ± 6 kg/m2 , and male sex 38%]. Mean IGF-1 Z-scores were higher in ACTIVE (3.9 ± 1.0) vs SSA and PEG, which did not differ from one another (0.5 ± 0.7 and 0.5 ± 0.7, P < .0001 vs ACTIVE). Eighty-three per cent of PEG previously received somatostatin analogs, which had been discontinued due to lack of efficacy (52%) or side effects (41%). There were no differences in the four QoL primary end-points (AcroQoL Global Score, SF-36 Physical Component Summary Score, SF-36 Mental Health Summary Score and GIQLI Global Score) between SSA and PEG. Higher HbA1c, BMI and IGF-1 Z-scores were associated with poorer QoL in several domains. CONCLUSION: Our data support a comparable QoL in patients receiving pegvisomant vs somatostatin analogs, despite the fact that the vast majority receiving pegvisomant did not respond to or were not able to tolerate somatostatin analogs.

Body composition predictors of skeletal integrity in obesity.

OBJECTIVE: To determine body composition predictors of skeletal integrity in overweight/obese subjects using dual energy X-ray absorptiometry (DXA). We hypothesized that visceral adiposity would be negatively, and lean mass positively, associated with DXA measures of skeletal integrity in obesity. MATERIALS AND METHODS: Our study was institutional review board (IRB)-approved and Health Insurance Portability and Accountability Act (HIPAA)-compliant and written informed consent was obtained. We studied 82 overweight or obese, but otherwise healthy premenopausal women and men of similar age who were part of a clinical trial (mean age: 37 ± 10 years, mean BMI: 34 ± 7 kg/m(2)). All subjects underwent DXA of the spine and hip for assessment of bone mineral density (BMD), trabecular bone score (TBS), and hip structural analysis (HSA), and of the whole body for the assessment of body composition, including estimated visceral adipose tissue (VAT). RESULTS: Sixty-three subjects (77 %) had normal BMD and 19 subjects (23 %) had osteopenia. There were strong age-, sex-, and BMD-independent positive associations between lean mass and HSA parameters (r = 0.50 to r = 0.81, p < 0.0001), whereas there was no association with TBS. There were strong age-, sex- and BMD-independent inverse associations between total fat and VAT mass and TBS (r = -0.60 and r = -0.72, p < 0.0001 for both correlations), whereas there were no associations with HSA parameters. CONCLUSION: Lean mass is a positive predictor of hip geometry, whereas fat and VAT mass are negative predictors of trabecular microarchitecture in overweight/obese subjects.

Higher serum myostatin levels are associated with lower insulin sensitivity in adults with overweight/obesity.

Myostatin inhibition improves insulin sensitivity in preclinical and clinical models; however, studies investigating the relationship between serum myostatin levels and insulin sensitivity are discrepant. Sensitive and specific myostatin LC-MS/MS assays are now available to accurately assess serum myostatin level in vivo. We sought to determine whether higher serum myostatin levels are independently associated with lower insulin sensitivity in adults with overweight/obesity. Participants included 74 adults, 20-65 years old, BMI ≥25 kg/m2 without type 2 diabetes. Appendicular lean mass (ALM) was measured by dual-energy x-ray absorptiometry; visceral adipose tissue (VAT) was measured by computed tomography. Main outcome measures were serum myostatin levels (LC-MS/MS) and insulin sensitivity (Matsuda index). Mean age was 48 ± 12 years, and BMI was 33.1 ± 5.6 kg/m2 (mean ± SD). Men had higher mean serum myostatin levels versus women (8.3 ± 1.9 vs. 7.2 ± 1.9 ng/mL, p = 0.01) and higher serum myostatin levels were associated with higher ALM (R = 0.34, p = 0.003). Higher serum myostatin levels were associated with lower Matsuda index (R = -0.44, p = 0.0004), which remained significant after controlling for BMI, VAT, ALM, and sex. In conclusion, higher serum myostatin levels are independently associated with lower insulin sensitivity in adults with overweight/obesity and may be a marker of or play a mechanistic role in the development of insulin resistance.

Ectopic and serum lipid levels are positively associated with bone marrow fat in obesity.

PURPOSE: To investigate the associations between ectopic and serum lipid levels and bone marrow fat, as a marker of stem cell differentiation, in young obese men and women, with the hypothesis that ectopic and serum lipid levels would be positively associated with bone marrow fat. MATERIALS AND METHODS: The study was institutional review board approved and complied with HIPAA guidelines. Written informed consent was obtained. The study group comprised 106 healthy young men and women (mean age, 33.7 years ± 6.8 [standard deviation]; range, 19-45 years; mean body mass index (BMI), 33.1 kg/m(2) ± 7.1; range, 18.1-48.8 kg/m(2)) who underwent hydrogen 1((1)H) magnetic resonance (MR) spectroscopy by using a point-resolved spatially localized spectroscopy sequence at 3.0 T of L4 for bone marrow fat content, of soleus muscle for intramyocellular lipids (IMCL), and liver for intrahepatic lipids (IHL), serum cholesterol level, serum triglyceride level, and measures of insulin resistance (IR). Exercise status was assessed with the Paffenbarger activity questionnaire. RESULTS: There was a positive correlation between bone marrow fat and IHL (r = 0.21, P = .048), IMCL (r = 0.27, P = .02), and serum triglyceride level (r = 0.33, P = .001), independent of BMI, age, IR, and exercise status (P < .05). High-density lipoprotein cholesterol levels were inversely associated with bone marrow fat content, independent of BMI, age, IR, and exercise status (r = -0.21, P = .019). CONCLUSION: Results of this study suggest that ectopic and serum lipid levels are positively associated with bone marrow fat in obese men and women.

Male Runners With Lower Energy Availability Have Impaired Skeletal Integrity Compared to Nonathletes.

CONTEXT: Female athletes, particularly runners, with insufficient caloric intake for their energy expenditure [low energy availability (EA) or relative energy deficiency] are at risk for impaired skeletal integrity. Data are lacking in male runners. OBJECTIVE: To determine whether male runners at risk for energy deficit have impaired bone mineral density (BMD), microarchitecture, and estimated strength. DESIGN: Cross-sectional. SETTING: Clinical research center. PARTICIPANTS: 39 men (20 runners, 19 controls), ages 16-30 years. MAIN OUTCOME MEASURES: Areal BMD (dual-energy x-ray absorptiometry); tibia and radius volumetric BMD and microarchitecture (high-resolution peripheral quantitative computed tomography); failure load (microfinite element analysis); serum testosterone, estradiol, leptin; energy availability. RESULTS: Mean age (24.5 ± 3.8 y), lean mass, testosterone, and estradiol levels were similar; body mass index, percent fat mass, leptin, and lumbar spine BMD Z-score (-1.4 ± 0.8 vs -0.8 ± 0.8) lower (P < .05); and calcium intake and running mileage higher (P ≤ .01) in runners vs controls. Runners with EA

Impact of GH administration on skeletal endpoints in adults with overweight/obesity.

Objective: Overweight/obesity is associated with relative growth hormone (GH) deficiency and increased fracture risk. We hypothesized that GH administration would improve bone endpoints in individuals with overweight/obesity. Design: An 18-month, randomized, double-blind, placebo-controlled study of GH, followed by 6-month observation. Methods: In this study, 77 adults (53% men), aged 18-65 years, BMI ≥ 25 kg/m2, and BMD T- or Z-score ≤ -1.0 were randomized to daily subcutaneous GH or placebo, targeting IGF1 in the upper quartile of the age-appropriate normal range. Forty-nine completed 18 months. DXA, volumetric quantitative CT, and high-resolution peripheral quantitative CT were performed. Results: Pre-treatment mean age (48 ± 12 years), BMI (33.1 ± 5.7 kg/m2), and BMD were similar between groups. P1NP, osteocalcin, and CTX increased (P < 0.005) and visceral adipose tissue decreased (P = 0.04) at 18 months in the GH vs placebo group. Hip and radius aBMD, spine and tibial vBMD, tibial cortical thickness, and radial and tibial failure load decreased in the GH vs placebo group (P < 0.05). Between 18 and 24 months (post-treatment observation period), radius aBMD and tibia cortical thickness increased in the GH vs placebo group. At 24 months, there were no differences between the GH and placebo groups in bone density, structure, or strength compared to baseline. Conclusions: GH administration for 18 months increased bone turnover in adults with overweight/obesity. It also decreased some measures of BMD, bone microarchitecture, and bone strength, which all returned to pre-treatment levels 6 months post-therapy. Whether GH administration increases BMD with longer treatment duration, or after mineralization of an expanded remodeling space post-treatment, requires further investigation.

Sex differences in body composition and association with cardiometabolic risk.

BACKGROUND: Body composition differs between men and women, with women having proportionally more fat mass and men more muscle mass. Although men and women are both susceptible to obesity, health consequences differ between the sexes. The purpose of our study was to assess sex differences in body composition using anatomic and functional imaging techniques, and its relationship to cardiometabolic risk markers in subjects with overweight/obesity. METHODS: After written informed consent, we prospectively recruited 208 subjects with overweight/obesity who were otherwise healthy (94 men, 114 women, age 37 ± 10 years, BMI 35 ± 6 kg/m2). Subjects underwent dual-energy X-ray absorptiometry (DXA) and computed tomography (CT) for fat and muscle mass, proton MR spectroscopy (1H-MRS) for intrahepatic (IHL) and intramyocellular lipids (IMCL), an oral glucose tolerance test, serum insulin, lipids, and inflammatory markers. Men and women were compared by Wilcoxon signed rank test. Linear correlation and multivariate analyses between body composition and cardiometabolic risk markers were performed. RESULTS: Women and men were of similar mean age and BMI (p ≥ 0.2). Women had higher %fat mass, extremity fat, and lower lean mass compared to men (p ≤ 0.0005). However, men had higher visceral adipose tissue (VAT) and IMCL and higher age-and BMI-adjusted IHL (p < 0.05). At similar age and BMI, men had a more detrimental cardiometabolic risk profile compared to women (p < 0.01). However, VAT in women, and IMCL in men, were more strongly associated with cardiometabolic risk markers, while more lower extremity fat was associated with a more favorable cardiometabolic profile in women compared to men (p ≤ 0.03). CONCLUSIONS: Although the male pattern of fat distribution is associated with a more detrimental cardiometabolic risk profile compared to women of similar age and BMI, VAT is more strongly associated with cardiometabolic risk markers in women, while IMCL are more detrimental in men. Lower extremity fat is relatively protective, in women more than in men. This suggests that detailed anatomic and functional imaging, rather than BMI, provides a more complete understanding of metabolic risk associated with sex differences in fat distribution.

The effect of growth hormone on bioactive IGF in overweight/obese women.

OBJECTIVE: Overweight/obesity is characterized by decreased growth hormone (GH) secretion whereas circulating IGF-I levels are less severely reduced. Yet, the activity of the circulating IGF-system appears to be normal in overweight/obese subjects, as estimated by the ability of serum to activate the IGF-I receptor in vitro (bioactive IGF). We hypothesized that preservation of bioactive IGF in overweight/obese women is regulated by an insulin-mediated suppression of IGF-binding protein-1 (IGFBP-1) and IGFBP-2, and by suppression of IGFBP-3, mediated by low GH. We additionally hypothesized that increases in bioactive IGF would drive changes in body composition with low-dose GH administration. DESIGN: Cross-sectional analysis and 3-month interim analysis of a 6-month randomized, placebo-controlled study of GH administration in 50 overweight/obese women without diabetes mellitus. Bioactive IGF (kinase receptor activation assay) and body composition (DXA) were measured. RESULTS: Prior to treatment, IGFBP-3 (r = -0.33, p = 0.02), but neither IGFBP-1 nor IGFBP-2, associated inversely with bioactive IGF. In multivariate analysis, lower IGFBP-3 correlated with lower peak stimulated GH (r = 0.45, p = 0.05) and higher insulin sensitivity (r = -0.74, p = 0.003). GH administration resulted in an increase in mean serum IGF-I concentrations (144 ±â€¯56 to 269 ±â€¯66 µg/L, p < 0.0001) and bioactive IGF (1.29 ±â€¯0.39 to 2.60 ±â€¯1.12 µg/L, p < 0.0001). The treatment-related increase in bioactive IGF, but not total IGF-I concentration, predicted an increase in lean mass (r = 0.31, p = 0.03) and decrease in total adipose tissue/BMI (r = -0.43, p = 0.003). CONCLUSIONS: Our data suggest that in overweight/obesity, insulin sensitivity and GH have opposing effects on IGF bioactivity through effects on IGFBP-3. Furthermore, increases in bioactive IGF, rather than IGF-I concentration, predicted GH administration-related body composition changes. CLINICAL TRIAL REGISTRATION NUMBER: NCT00131378.

GH administration decreases subcutaneous abdominal adipocyte size in men with abdominal obesity.

OBJECTIVE: To investigate the effects of short-term GH administration on abdominal subcutaneous adipocyte size and CT attenuation in men with abdominal obesity. DESIGN: 6-week, randomized, double-blind, placebo-controlled study of GH (starting dose 2µg/kg/d) vs placebo of 15 abdominally obese men (mean age: 34±6years; mean BMI: 37.7±6.1kg/m2, mean IGF-1 SDS: -1.9±0.5) who underwent abdominal subcutaneous adipose tissue (SAT) aspirations to determine adipocyte size, CTs for body composition and measures of glucose tolerance at baseline and 6weeks. GH dosing was titrated to target IGF-1 levels in the upper normal age-appropriate range. RESULTS: GH administration decreased subcutaneous abdominal adipocyte size compared to placebo. Adipocyte size was positively associated with 120-min glucose and HOMA-IR and inversely associated with peak-stimulated GH and CT attenuation. CT attenuation of SAT was inversely associated with 120-min glucose and HOMA-IR and increased following GH administration. CONCLUSION: In men with abdominal obesity, subcutaneous abdominal adipocyte size is positively associated with measures of impaired glucose tolerance and administration of GH at doses that raise IGF-1 levels within the normal range, decreases abdominal subcutaneous adipocyte size, suggesting that GH administration improves the health of adipose tissue. Clinical trials number: NCT00131378.

Body Composition and Ectopic Lipid Changes With Biochemical Control of Acromegaly.

Context: Acromegaly is characterized by growth hormone (GH) and insulinlike growth factor-1 (IGF-1) hypersecretion, and GH and IGF-1 play important roles in regulating body composition and glucose homeostasis. Objective: The purpose of our study was to investigate body composition including ectopic lipids, measures of glucose homeostasis, and gonadal steroids in patients with active acromegaly compared with age-, body mass index (BMI)-, and sex-matched controls and to determine changes in these parameters after biochemical control of acromegaly. Design: Cross-sectional study of 20 patients with active acromegaly and 20 healthy matched controls. Prospective study of 16 patients before and after biochemical control of acromegaly. Main Outcome Measures: Body composition including ectopic lipids by magnetic resonance imaging/proton magnetic resonance spectroscopy; measures of glucose homeostasis by an oral glucose tolerance test; gonadal steroids. Results: Patients with active acromegaly had lower mean intrahepatic lipid (IHL) and higher mean fasting insulin and insulin area under the curve (AUC) values than controls. Men with acromegaly had lower mean total testosterone, sex hormone-binding globulin, and estradiol values than male controls. After therapy, homeostasis model assessment of insulin resistance, fasting insulin level, and insulin AUC decreased despite an increase in IHL and abdominal and thigh adipose tissues and a decrease in muscle mass. Conclusions: Patients with acromegaly were characterized by insulin resistance and hyperinsulinemia but lower IHL compared with age-, BMI-, and sex-matched healthy controls. Biochemical control of acromegaly improved insulin resistance but led to a less favorable anthropometric phenotype with increased IHL and abdominal adiposity and decreased muscle mass.

Bone microarchitecture and estimated bone strength in men with active acromegaly.

CONTEXT: Both acromegaly and adult growth hormone deficiency (GHD) are associated with increased fracture risk. Sufficient data are lacking regarding cortical bone microarchitecture and bone strength, as assessed by microfinite element analysis (µFEA). OBJECTIVE: To elucidate both cortical and trabecular bone microarchitecture and estimated bone strength in men with active acromegaly or GHD compared to healthy controls. DESIGN AND SUBJECTS: Cross-sectional study at a clinical research center, including 48 men (16 with acromegaly, 16 with GHD and 16 healthy controls). OUTCOME MEASURES: Areal bone mineral density (aBMD), cortical and trabecular bone microarchitecture and estimated bone strength (µFEA) at the radius and tibia. RESULTS: aBMD was not different between the 3 groups at any skeletal site. At the radius, patients with acromegaly had greater cortical area (P < 0.0001), cortical thickness (P = 0.0038), cortical pore volume (P < 0.0001) and cortical porosity (P = 0.0008), but lower trabecular bone density (P = 0.0010) compared to controls. At the tibia, patients with acromegaly had lower trabecular bone density (P = 0.0082), but no differences in cortical bone microstructure. Compressive strength and failure load did not significantly differ between groups. These findings persisted after excluding patients with hypogonadism. Bone microarchitecture was not deficient in patients with GHD. CONCLUSIONS: Both cortical and trabecular microarchitecture are altered in men with acromegaly. Our data indicate that GH excess is associated with distinct effects in cortical vs trabecular bone compartments. Our observations also affirm the limitations of aBMD testing in the evaluation of patients with acromegaly.

Vertebral Volumetric Bone Density and Strength Are Impaired in Women With Low-Weight and Atypical Anorexia Nervosa.

Context: Areal bone mineral density (BMD) is lower, particularly at the spine, in low-weight women with anorexia nervosa (AN). However, little is known about vertebral integral volumetric BMD (Int.vBMD) or vertebral strength across the AN weight spectrum, including "atypical" AN [body mass index (BMI) ≥18.5 kg/m2]. Objective: To investigate Int.vBMD and vertebral strength, and their determinants, across the AN weight spectrum. Design: Cross-sectional observational study. Setting: Clinical research center. Participants: 153 women (age 18 to 45): 64 with low-weight AN (BMI <18.5 kg/m2; 58% amenorrheic), 44 with atypical AN (18.5≤BMI<23 kg/m2; 30% amenorrheic), 45 eumenorrheic controls (19.2≤BMI<25 kg/m2). Measures: Int.vBMD and cross-sectional area (CSA) by quantitative computed tomography of L4; estimated vertebral strength (derived from Int.vBMD and CSA). Results: Int.vBMD and estimated vertebral strength were lowest in low-weight AN, intermediate in atypical AN, and highest in controls. CSA did not differ between groups; thus, vertebral strength (calculated using Int.vBMD and CSA) was driven by Int.vBMD. In AN, Int.vBMD and vertebral strength were associated positively with current BMI and nadir lifetime BMI (independent of current BMI). Int.vBMD and vertebral strength were lower in AN with current amenorrhea and longer lifetime amenorrhea duration. Among amenorrheic AN, Int.vBMD and vertebral strength were associated positively with testosterone. Conclusions: Int.vBMD and estimated vertebral strength (driven by Int.vBMD) are impaired across the AN weight spectrum and are associated with low BMI and endocrine dysfunction, both current and previous. Women with atypical AN experience diminished vertebral strength, partially due to prior low-weight and/or amenorrhea. Lack of current low-weight or amenorrhea in atypical AN does not preclude compromise of vertebral strength.

Association between adiposity and cognitive function in young men: Hormonal mechanisms.

OBJECTIVE: To determine the association between adiposity, hormones, and cognition in young men with abdominal obesity. METHODS: In this cross-sectional observational study, 53 nondiabetic men with abdominal obesity (mean body mass index, 37.3 kg/m(2) ; age, 22-45 years) and normal intelligence underwent detailed measures of body composition, hormonal profiles, and cognition. Age- and education-adjusted performance in five cognitive domains was examined. RESULTS: Total fat percentage was negatively associated with visuospatial skills (P = 0.002) and visual memory (P = 0.012). Insulin resistance (homeostatic model assessment of insulin resistance) was also negatively associated with these domains (P = 0.05 and trend, P = 0.06, respectively). Total testosterone levels were negatively associated with executive function and verbal learning and memory (P = 0.04 for each), but free testosterone was not. Sex hormone-binding globulin (SHBG) was also inversely associated with performance in these domains (P = 0.015 and trend, P = 0.09, respectively). In a stepwise regression model including percentage fat, homeostatic model assessment of insulin resistance, SHBG, and free testosterone, SHBG was the only variable selected for executive function (P = 0.05) and showed a trend for verbal learning and memory (P = 0.09). CONCLUSIONS: Adiposity and insulin resistance were associated with worse function in visual domains. An unexpected negative association is reported between SHBG and cognitive measures, which seemed to be independent of free testosterone levels.

Effect of growth hormone treatment on diastolic function in patients who have developed growth hormone deficiency after definitive treatment of acromegaly.

OBJECTIVE: Although growth hormone (GH) replacement is prescribed for patients with hypopituitarism due to many etiologies, it is not routinely prescribed for patients with GH deficiency (GHD) after cure of acromegaly (acroGHD). This study was designed to investigate the effect of GH replacement on cardiac parameters in acroGHD. DESIGN: We prospectively evaluated for 12months 23 patients with acroGHD: 15 subjects on GH replacement and eight subjects not on GH replacement. Main outcome measures included LV mass corrected for body surface area (LVM/BSA) and measures of diastolic dysfunction (E/A ratio and deceleration time), as assessed by echocardiography. RESULTS: After 12months of follow-up, there were no differences between the GH-treated group and the untreated group in LVM/BSA (GH: 74.4±22.5g/m(2) vs untreated: 72.9±21.3g/m(2), p=0.89), E/A ratio (GH: 1.21±0.39 vs untreated: 1.08±0.39, p=0.50) or deceleration time (GH: 224.5±60.1ms vs untreated: 260±79.8ms, p=0.32). The overall degree of diastolic function was similar between the groups with 42.9% of untreated subjects and 50% of GH-treated subjects (p=0.76) classified as having normal diastolic function at follow-up. CONCLUSIONS: There were no significant differences in LVM/BSA or parameters of diastolic function in patients with a history of acromegaly treated for GHD as compared to those who were untreated. These data are reassuring with respect to cardiovascular safety with GH use after treatment for acromegaly, although further longer term study is necessary to evaluate the safety and efficacy of GH treatment in this population.

Vertebral Strength and Estimated Fracture Risk Across the BMI Spectrum in Women.

Somewhat paradoxically, fracture risk, which depends on applied loads and bone strength, is elevated in both anorexia nervosa and obesity at certain skeletal sites. Factor-of-risk (Φ), the ratio of applied load to bone strength, is a biomechanically based method to estimate fracture risk; theoretically, higher Φ reflects increased fracture risk. We estimated vertebral strength (linear combination of integral volumetric bone mineral density [Int.vBMD] and cross-sectional area from quantitative computed tomography [QCT]), vertebral compressive loads, and Φ at L4 in 176 women (65 anorexia nervosa, 45 lean controls, and 66 obese). Using biomechanical models, applied loads were estimated for: 1) standing; 2) arms flexed 90°, holding 5 kg in each hand (holding); 3) 45° trunk flexion, 5 kg in each hand (lifting); 4) 20° trunk right lateral bend, 10 kg in right hand (bending). We also investigated associations of Int.vBMD and vertebral strength with lean mass (from dual-energy X-ray absorptiometry [DXA]) and visceral adipose tissue (VAT, from QCT). Women with anorexia nervosa had lower, whereas obese women had similar, Int.vBMD and estimated vertebral strength compared with controls. Vertebral loads were highest in obesity and lowest in anorexia nervosa for standing, holding, and lifting (p < 0.0001) but were highest in anorexia nervosa for bending (p < 0.02). Obese women had highest Φ for standing and lifting, whereas women with anorexia nervosa had highest Φ for bending (p < 0.0001). Obese and anorexia nervosa subjects had higher Φ for holding than controls (p < 0.03). Int.vBMD and estimated vertebral strength were associated positively with lean mass (R = 0.28 to 0.45, p ≤ 0.0001) in all groups combined and negatively with VAT (R = -[0.36 to 0.38], p < 0.003) within the obese group. Therefore, women with anorexia nervosa had higher estimated vertebral fracture risk (Φ) for holding and bending because of inferior vertebral strength. Despite similar vertebral strength as controls, obese women had higher vertebral fracture risk for standing, holding, and lifting because of higher applied loads from higher body weight. Examining the load-to-strength ratio helps explain increased fracture risk in both low-weight and obese women.

Effects of growth hormone administration for 6 months on bone turnover and bone marrow fat in obese premenopausal women.

PURPOSE: Abdominal adiposity is associated with low BMD and decreased growth hormone (GH) secretion, an important regulator of bone homeostasis. The purpose of our study was to determine the effects of a short course of GH on markers of bone turnover and bone marrow fat in premenopausal women with abdominal adiposity. MATERIALS AND METHODS: In a 6-month, randomized, double-blind, placebo-controlled trial we studied 79 abdominally obese premenopausal women (21-45 y) who underwent daily sc injections of GH vs. placebo. Main outcome measures were body composition by DXA and CT, bone marrow fat by proton MR spectroscopy, P1NP, CTX, 25(OH)D, hsCRP, undercarboxylated osteocalcin (ucOC), preadipocyte factor 1 (Pref 1), apolipoprotein B (ApoB), and IGF-1. RESULTS: GH increased IGF-1, P1NP, 25(OH)D, ucOC, bone marrow fat and lean mass, and decreased abdominal fat, hsCRP, and ApoB compared with placebo (p<0.05). There was a trend toward an increase in CTX and Pref-1. Among all participants, a 6-month increase in IGF-1 correlated with 6-month increase in P1NP (p=0.0005), suggesting that subjects with the greatest increases in IGF-1 experienced the greatest increases in bone formation. A six-month decrease in abdominal fat, hsCRP, and ApoB inversely predicted 6-month change in P1NP, and 6-month increase in lean mass and 25(OH)D positively predicted 6-month change in P1NP (p≤0.05), suggesting that subjects with greatest decreases in abdominal fat, inflammation and ApoB, and the greatest increases in lean mass and 25(OH)D experienced the greatest increases in bone formation. A six-month increase in bone marrow fat correlated with 6-month increase in P1NP (trend), suggesting that subjects with the greatest increases in bone formation experienced the greatest increases in bone marrow fat. Forward stepwise regression analysis indicated that increase in lean mass and decrease in abdominal fat were positive predictors of P1NP. When IGF-1 was added to the model, it became the only predictor of P1NP. CONCLUSION: GH replacement in abdominally obese premenopausal women for 6 months increased bone turnover and bone marrow fat. Reductions in abdominal fat, and inflammation, and increases in IGF-1, lean mass and vitamin D were associated with increased bone formation. The increase in bone marrow fat may reflect changes in energy demand from increased bone turnover.

Overweight/Obese adults with pituitary disorders require lower peak growth hormone cutoff values on glucagon stimulation testing to avoid overdiagnosis of growth hormone deficiency.

CONTEXT: Obesity is associated with diminished GH secretion, which may result in the overdiagnosis of adult GH deficiency (GHD) in overweight/obese pituitary patients. However, there are no body mass index (BMI)-specific peak GH cutoffs for the glucagon stimulation test (GST), the favored dynamic test for assessing adult GHD in the United States. OBJECTIVE: The objective of the study was to determine a peak GH cutoff level for the diagnosis of adult GHD in overweight/obese individuals using the GST. DESIGN: This was a retrospective, cross-sectional study. SETTING: The study was conducted at Massachusetts General Hospital and Oregon Health and Science University. METHODS: A total of 108 subjects with a BMI ≥ 25 kg/m(2) were studied: healthy controls (n = 47), subjects with total pituitary deficiency (TPD) (n = 20, ≥ 3 non-GH pituitary hormone deficiencies), and subjects with partial pituitary deficiency (PPD) (n = 41, 1-2 non-GH pituitary hormone deficiencies). INTERVENTION: The intervention consisted of a standard 4-hour GST. MAIN OUTCOME MEASURES: The main outcome measure was peak GH level on GST. RESULTS: Using the standard peak GH cutoff of 3 ng/mL, 95% of TPD cases (19 of 20), 80% of PPD (33 of 41), and 45% of controls (21 of 47) were classified as GHD. In receiver-operator characteristic curve analysis (controls vs TPD), a peak GH value of 0.94 ng/mL provided the greatest sensitivity (90%) and specificity (94%). Using a peak GH cutoff of 1 ng/mL, 6% of controls (3 of 47), 59% of PPDs (24 of 41), and 90% of TPDs (18 of 20) were classified as GHD. BMI (R = -0.35, P = .02) and visceral adipose tissue (R = -0.32, P = .03) negatively correlated with peak GH levels in controls. CONCLUSION: A large proportion of healthy overweight/obese individuals (45%) failed the GST using the standard 3 ng/mL GH cutoff. Overweight/obese pituitary patients are at risk of being misclassified as GHD using this cutoff level. A 1-ng/mL GH cutoff may reduce the overdiagnosis of adult GHD in overweight/obese patients.