GH Cutoff Research Articles

Children with Attention Deficit Hyperactivity Disorder Are More Likely to Fail Growth Hormone Stimulation Testing than Children without Attention Deficit Hyperactivity Disorder: A Retrospective Chart Review

Introduction: Children with ADHD often present to pediatric endocrinologists due to growth concerns. Growth hormone stimulation testing (GHST) may be utilized as part of the workup. We evaluate whether children with ADHD and short stature or growth failure are more likely to fail GHST compared to children without ADHD. Methods: We retrospectively studied children who underwent GHST as part of evaluation for short stature and/or growth failure and had an intact pituitary over a 16-year period (2002–2018). We performed univariate and logistic regression analyses with stratification by age. Results: We included 260 children; 78 children had ADHD and were older, mean age (±SD) 12.2 (±2.6) years versus children without ADHD, mean age (±SD) 10.4 (±3.8) years. The population was largely Caucasian, and boys outnumbered the girls. Of the children with ADHD, only 9 were not medically treated. There was no difference in z-scores for height, weight, and BMI, or mid-parental height between the two groups. We found that children with ADHD were more likely to fail GHST than children without ADHD across the peak GH cut-offs of 10, 7, and 5 ng/mL (p = 0.003, p = 0.023, and p = 0.046 accordingly). The same trend persisted after regression analysis with adjustment for sex and stratification by age, and effect was more robust in the older group. Discussion: The result shows higher likelihood of lower GH peaks in response to GHST in children with ADHD and short stature or impaired linear growth. Future work should evaluate possible mechanistic explanation and the role of psycho-stimulant medications.

The landscape of retesting in childhood-onset idiopathic growth hormone deficiency and its reversibility: a systematic review and meta-analysis.

Children diagnosed with idiopathic isolated growth hormone deficiency (IGHD) are frequently observed to no longer be GH-deficient at a later stage of growth as a result of 'GHD reversal'. Reevaluation of GH status by stimulation test is currently incorporated into management guidelines at attainment of final height (FH). Over the past three decades, numerous studies have evaluated reversal rates using different methodologies including crucial parameters like GHD aetiology, GH cut-off and retesting time point, with heterogeneous results. We aimed to systematically analyse the reversibility of childhood-onset IGHD dependent on retesting GH cut-offs and retesting time points. PubMed, Cochrane Library, TRIP database and NHS Evidence were searched for publications investigating the reversibility of IGHD from database initiation to 30 June 2020 following PRISMA recommendations. Study cohorts were pooled according to retesting GH cut-off and time point. Reversal rates were calculated using random-effects models. Of the 29 studies initially identified, 25 provided sufficient detail for IGHD analysis, resulting in 2030 IGHD patient data. Reversal rates decreased significantly as the retesting GH cut-off increased (P = 0.0013). Pooled (95% CI) reversal rates were 80% (59-92%, n = 227), 73% (62-81%, n = 516) and 55% (41-68%, n = 1287) for cohorts using retesting GH cut-offs of 3-4 ng/mL, 5-6 ng/mL and 7.7-10 ng/mL, respectively. Individuals retested at FH (n = 674) showed a pooled reversal rate of 74% (64-82%) compared to 48% (25-71%) when retested before FH (n = 653). Provided evidence supports reevaluation of current IGHD management guidelines. The high reversal rates should instigate consideration of early retesting.

Adult height after treatment of neurosecretory dysfunction and comparison to idiopathic GHD.

Neurosecretory dysfunction (NSD) causes growth hormone deficiency (GHD). Data on adult height after recombinant human growth hormone (rhGH) treatment are lacking. We collected treatment data of all patients with NSD seen between 1990 and 2017 at our outpatient department (tertiary centre) and measured adult height. For comparison, patients with idiopathic GHD were used. Diagnoses were based on short stature (<-2 standard deviation score [SDS]), continuously low height velocity (<25th percentile), delayed bone age (by >1 SD) and low serum IGF-1 concentration (<-2 SDS). NSD was defined by normal GH challenge results, but subnormal spontaneous GH secretion. Exclusion criteria were no information on adult height, underweight and other short stature disorders. Out of 67 patients diagnosed with NSD, six were still growing, 31 had test results exceeding validated GH cut-offs and three had other disorders causing short stature. Out of the 25 eligible patients with NSD, 21 could be recruited. These patients reached an adult height of -0.85 SDS (mean); 0.34 SDS below midparental height. Height gain during treatment was 2.01 SDS. This outcome was not different to 32 patients with idiopathic GHD. Long-term results suggest the viability of the diagnosis of NSD and the efficacy of rhGH treatment.

Glucagon stimulation test to assess growth hormone status in Prader\u2013Willi syndrome

PurposeGrowth hormone deficiency (GHD) must be confirmed before starting treatment in adults with Prader-Willi syndrome (PWS). Most studies use the growth-hormone-releasing hormone plus arginine (GHRH-arginine) test. No data are available on the glucagon stimulation test (GST) in PWS. We compared the utility of fixed-dose (1 mg) GST versus GHRH-arginine test in diagnosing GHD.MethodsAdults and late adolescents with PWS underwent both tests on separate days. In the GHRH-arginine test, GHD was defined according to body mass index. In the GST, two cutoffs were analyzed: peak GH concentration < 3 ng/mL and < 1 ng/mL. For analyses, patients were divided into two groups according to body weight (≤ 90 kg and > 90 kg).ResultsWe analyzed 34 patients: 22 weighing ≤ 90 kg and 12 weighing > 90 kg. In patients weighing ≤ 90 kg, the two tests were concordant in 16 (72.72%) patients (k = 0.476, p = 0.009 with GST cutoff < 3 ng/mL, and k = 0.450, p = 0.035 with GST cutoff < 1 ng/mL). In patients weighing > 90 kg, the two tests were not concordant with GST cutoff < 3 ng/mL, but were concordant in 11 (91.6%) patients (k = 0.833, p = 0.003) with GST cutoff < 1 ng/mL. GH peaks on the two tests correlated (r = 0.725, p = 0.008).ConclusionFixed-dose (1 mg) GST using a peak GH cutoff of < 3 ng/mL or < 1 ng/mL promises to be useful for screening for GHD in adults and late adolescents with PWS. However, in those weighing > 90 kg, the < 1 ng/mL cutoff seems better. Larger studies are necessary to establish definitive glucagon doses and cutoffs, especially in extremely obese patients.

GHD Diagnostics in Europe and the US: An Audit of National Guidelines and Practice

Introduction: Almost 20 years after the first international guidelines on the diagnosis and treatment of GHD have been published, clinical practice varies significantly. The low accuracy of endocrine tests for GHD and the burden caused by ineffective treatment of individual patients were strong motives for national endocrine societies to set up national guidelines regarding how to diagnose GHD in childhood. This audit aims to review the current state and identify common changes, which may improve the diagnostic procedure. Methods: A group of eight German pediatric endocrinologists contacted eight pediatric endocrinologists from Spain, France, Poland, the UK, the Netherlands, Denmark, Italy, and the US. Each colleague responded as a representative for the own country to a detailed questionnaire containing 22 open questions about national rules, guidelines, and practice with respect to GHD diagnostics and GH prescription. The results were presented and discussed in a workshop and then documented in this study which was reviewed by all participants. Results: National guidelines are available in 7 of 9 countries. GH is prescribed by pediatric endocrinologists in most countries. Some countries have established boards that review and monitor prescriptions. Preferred GH stimulation tests and chosen cutoffs vary substantially. Overall, a trend to lowering the GH cutoff was identified. Priming is becoming more popular and now recommended in 5 out of 9 countries; however, with different protocols. The definition of pretest-conditions that qualify the patient to undergo GH testing varies substantially in content and strictness. The most frequently used clinical sign is low height velocity, but definition varies. Height, IGF-1, and bone age are additional parameters recommended in some countries. Conclusions: GHD diagnostics varies substantially in eight European countries and in the US. It seems appropriate to undertake further efforts to harmonize endocrine diagnostics in Europe and the US based on available scientific evidence.

Prevalence of growth hormone deficiency in middle-age adults recovering from stroke

ABSTRACTObjective: The prevalence of chronic growth hormone deficiency (GHD) and its association with other hormonal deficiencies was determined in middle-aged patients post-stroke with and without consideration of body mass index (BMI).Methods: Clinical records were reviewed to determine pituitary function at least 3 months post-stroke. Patients with a history of endocrine anomalies were excluded. GHD was determined by utilizing standard peak GH cutoffs following the glucagon stimulation test. A secondary analysis was conducted with stricter BMI-adjusted cutoffs. The accuracy of IGF-1 in predicting GHD was also examined.Results: GHD was diagnosed in 54% of patients (≥5.0 μg/L), with 32% falling into the severe (≤3 μg/L) category. Patients with GHD had lower levels of FSH, T3, LH, and SHBG. Analyzes of BMI-adjusted GH levels, revealed that 14% of patients were GHD. These patients had higher prolactin. IGF-1 values were not predictive of GHD. Latency to be admitted to post-acute rehabilitation was greater in patients with GHD.Conclusions: Evidence suggests patients with stroke may be at risk for developing GHD. GHD was associated with decreased levels of other hormones. Co-morbidities for stroke and neuroendocrine dysfunction overlap and may have implications for recovery following stroke.

OR16-1 Best of The Journal of Clinical Endocrinology & Metabolism: Macimorelin as a Diagnostic Test for Adult GH Deficiency

"Best of" The Journal of Clinical Endocrinology & Metabolism, Volume 103, Issue 8, 1 August 2018, Pages 3083-3093, https://doi.org/10.1210/jc.2018-00665. Purpose: The diagnosis of adult GH deficiency (AGHD) is challenging and often requires confirmation with a GH stimulation test (GHST). The insulin tolerance test (ITT) is considered the reference standard GHST but is labor intensive, can cause severe hypoglycemia, and is contraindicated for certain patients. Macimorelin, an orally active GH secretagogue, could be used to diagnose AGHD by measuring stimulated GH levels after an oral dose. Materials and Methods: The present multicenter, open-label, randomized, two-way crossover trial was designed to validate the efficacy and safety of single-dose oral macimorelin for AGHD diagnosis compared with the ITT. Subjects with high (n = 38), intermediate (n = 37), and low (n = 39) likelihood for AGHD and healthy, matched controls (n = 25) were included in the efficacy analysis. Results: After the first test, 99% of macimorelin tests and 82% of ITTs were evaluable. Using GH cutoff levels of 2.8 ng/mL for macimorelin and 5.1 ng/mL for ITTs, the negative agreement was 95.38% (95% CI, 87% to 99%), the positive agreement was 74.32% (95% CI, 63% to 84%), sensitivity was 87%, and specificity was 96%. On retesting, the reproducibility was 97% for macimorelin (n = 33). In post hoc analyses, a GH cutoff of 5.1 ng/mL for both tests resulted in 94% (95% CI, 85% to 98%) negative agreement, 82% (95% CI, 72% to 90%) positive agreement, 92% sensitivity, and 96% specificity. No serious adverse events were reported for macimorelin. Conclusions: Oral macimorelin is a simple, well-tolerated, reproducible, and safe diagnostic test for AGHD with accuracy comparable to that of the ITT. A GH cutoff of 5.1 ng/mL for the macimorelin test provides an excellent balance between sensitivity and specificity.

MON-451 Growth Hormone Deficiency (GHD) over 4 Years after Mild Traumatic Brain Injury (mTBI) in Deployed Veterans: Interim Review

Introduction: mTBI is associated with anterior pituitary hormone dysfunction. The potential long-term effect of this injury on pituitary function in Veterans is not clear. Methods: We present an interim report of our 4-year longitudinal prospective pilot study of pituitary function in Veterans diagnosed with mTBI. Of the 34 mTBI Veterans enrolled, we have tested 28 of them (4 female, 24 male; mean±SD age and BMI, 31.1±7.0 years and 30.2±6.2, respectively) for baseline pituitary hormone levels and cortisol response to ACTH. In 22 subjects growth hormone response to glucagon stimulation (GST) was tested at baseline. The same baseline data were obtained for 15 age-, sex-, deployment- and BMI-matched control subjects without mTBI (2 female,13 male; mean±SD age and BMI 33.9±6.8 years and 32.7±7.2, respectively). Follow-up testing has been done for 18 mTBI subjects in Year 1, 13 subjects in Year 2, 8 subjects in Year 3 and 3 subjects in Year 4. GH cutoffs of <1ng/mL for patients with a BMI≥25, and ≤ 3 ng/mL for a BMI < 25 were used for the diagnosis of GHD. Results: GHD was present in 9% (2/22) at baseline, 22% (4/18) at Year 1, 8% (1/13) at Year 2, 22% (2/9) at Year 3, and 0% (0/3) at Year 4. GHD did not occur in the same subject in subsequent years, and it appeared to recover within a year. The peak GST GH level for all subjects at each year trended downward from baseline to Years 1, 2, 3, and 4: (ng/mL, mean±SD) 7.6±7.7; 7.5±13.0; 3.5±3.3; 4.4±4.3; 1.9±0.9, respectively. Secondary hypogonadism occurred in 11%, 6%, 8% of subjects at baseline, Year 1 and Year 2, respectively; none has been found in Years 3 and 4. There are no subjects identified with hypothyroidism or overt adrenal insufficiency at baseline or over 4 years. Unexpectedly, GHD was detected in 27% (4/15) of control subjects. The mean±SD BMI of 39.4±7.8 for these subjects was higher than the BMI values for GH sufficient (GHS) control subjects (30.2±5.2), mTBI patients with GHD (29.6±4.6) and GHS (30.9±6.2). Secondary hypogonadism was present in 14%, and there were no cases of hypothyroidism or adrenal insufficiency. Conclusions: GHD occurs in patients with mTBI at up to 3 years of observation using the stricter GH cutoff criterion with a BMI ≥25. Because each patient with GHD in a particular year was unique, the cumulative occurrence of GHD thus far is 41% (9/22) over 4 years. The highest prevalence was in Year 2. Each subject appeared to recover from GHD in one year. Attrition of subjects has decreased the later year numbers; a more complete review will be possible when the remaining subject testing is completed. The detection of GHD in the non-mTBI control group suggests there may be additional factors in deployment itself that can put military personnel at risk. BMI as a confounding factor with the GST or any GH testing cannot be excluded. Identification of GHD and hypogonadism in Veterans with mTBI will provide treatment opportunities to enhance their recovery.

Cut-off limits of the peak GH response to stimulation tests for the diagnosis of GH deficiency in children and adolescents: study in patients with organic GHD.

The diagnosis of GH deficiency (GHD) in children and adolescents is established when GH concentrations fail to reach an arbitrary cut-off level after at least two provocative tests. The objective of the study was to define the optimal GH cut-offs to provocative tests in children and adolescents. Retrospective study in 372 subjects who underwent evaluation of GH secretion. GH and IGF-I were measured by chemiluminescence assay in all samples. Receiver operating characteristic (ROC) analysis was used to evaluate the optimal GH cut-offs and the diagnostic accuracy of provocative tests. Seventy four patients with organic GHD (GH peak <10μg/L after two provocative tests) and 298 control subjects (GH response >10μg/L to at least one test) were included in the study. The provocative tests used were arginine, insulin tolerance test (ITT) and clonidine. Diagnostic criteria based on cut-offs identified by ROC analysis (best pair of values for sensitivity and specificity) were evaluated for each test individually and for each test combined with IGF-I SDS. The optimal GH cut-off for arginine resulted 6.5μg/L, 5.1μg/L for ITT and 6.8μg/L for clonidine. IGF-I SDS has low accuracy in diagnosing GHD (AUC=0.85). The combination of the results of provocative tests with IGF-I concentrations increased the specificity. The results of the ROC analysis showed that the cut-off limits which discriminate between normal and GHD are lower than those commonly employed. IGF-I is characterized by low diagnostic accuracy.

Growth hormone responses to provocative tests in children with short stature.

Growth hormone deficiency (GHD) is defined as a serum peak GH concentration <10 ng/mL with provocation as tested by a combination of at least two separate tests. The aim of this study was to compare two standard tests, insulin and levodopa (L-dopa), with a primary focus on specificity and accuracy. Clinical data were collected retrospectively from a review of 120 children who visited the pediatric endocrine clinic at Chonnam National University Hospital for the evaluation of short stature between January 2006 and April 2014. Subjects underwent GH provocation tests with insulin and L-dopa. Blood samples were obtained at 0, 15, 30, 45, 60, 90, and 120 min after administration, and GH levels were measured. In the insulin test, serial glucose levels were also checked, closely monitoring hypoglycemia. A total of 83 children (69.2%) were diagnosed with GHD and 37 children (30.8%) were diagnosed with idiopathic short stature (ISS). Peak GH levels were achieved an average of 45 min after the administration of insulin and L-dopa for both groups. The specificity and accuracy were 78.4% and 93.6% for the insulin test and 29.7% and 79.2% for L-dopa test, respectively. In the ISS group, the cumulative frequency of a GH cutoff value of >10 ng/mL at 120 min was 75.6% after insulin stimulation compared with 35.1% after L-dopa stimulation. Considering these results, we recommend performing the insulin test first to exclude ISS and then the L-dopa test for the diagnosis of GHD. This way, ISS patients are diagnosed after a single test, thus reducing hospital days and the burden of undergoing two serial tests.

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

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. 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. This was a retrospective, cross-sectional study. The study was conducted at Massachusetts General Hospital and Oregon Health and Science University. 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). The intervention consisted of a standard 4-hour GST. The main outcome measure was peak GH level on GST. 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. 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.

Clinical evidence-based cutoff limits for GH stimulation tests in children with a backup of results with reference to mass spectrometry.

Cutoff limits of GH stimulation tests to diagnose GH deficiency (GHD) in children and adolescents are not sufficiently validated by clinical studies due to discrepancies in the performance of GH immunoassays and lack of available study populations. We aimed to establish new cutoff limits for GH stimulation tests based on clinical evidence and compared these immunoassay-based values with an antibody-independent mass spectrometric method. In a retrospective study, GH cutoff limits for eight different immunoassays and isotope dilution mass spectrometry (ID-MS) were calculated from hGH peak concentrations of short-statured children with and without GHD. We compared the serum GH peak concentrations at GH stimulation test of 52 short-statured children and adolescents, who have normal GH secretion at initial workup and normal growth in the follow-up, with the serum GH peak concentrations of 44 GHD patients in the same age range, in order to optimize the cutoff limit calculation. Discriminant analysis of re-measured GH led to a new cutoff limit of 7.09 μg/l using the iSYS assay (IDS) and the limits for the other seven hGH assays varied between 4.32 and 7.77 μg/l. For ID-MS, cutoffs of 5.48 μg/l (22k GH) and 7.43 μg/l (total GH) were ascertained. The establishment of method-specific clinical evidence-based GH cutoff limits is of importance to ensure adequate clinical diagnosis and treatment of children and adolescents with GHD. ID-MS may become an important tool for providing both reliable and sustainable SI traceability of GH measurements in the future.

Prevalence of Pituitary Hormone Dysfunction, Metabolic Syndrome, and Impaired Quality of Life in Retired Professional Football Players: A Prospective Study

Hypopituitarism is common after moderate and severe traumatic brain injury (TBI). Herein, we address the association between mild TBI (mTBI) and pituitary and metabolic function in retired football players. Retirees 30-65 years of age, with one or more years of National Football League (NFL) play and poor quality of life (QoL) based on Short Form 36 (SF-36) Mental Component Score (MCS) were prospectively enrolled. Pituitary hormonal and metabolic syndrome (MetS) testing was performed. Using a glucagon stimulation test, growth hormone deficiency (GHD) was defined with a standard cut point of 3 ng/mL and with a more stringent body mass index (BMI)-adjusted cut point. Subjects with and without hormonal deficiency (HD) were compared in terms of QoL, International Index of Erectile Function (IIEF) scores, metabolic parameters, and football career data. Of 74 subjects, 6 were excluded because of significant non-football-related TBIs. Of the remaining 68 subjects (mean age, 47.3±10.2 years; median NFL years, 5; median NFL concussions, 3; mean BMI, 33.8±6.0), 28 (41.2%) were GHD using a peak GH cutoff of <3 ng/mL. However, with a BMI-adjusted definition of GHD, 13 of 68 (19.1%) were GHD. Using this BMI-adjusted definition, overall HD was found in 16 (23.5%) subjects: 10 (14.7%) with isolated GHD; 3 (4.4%) with isolated hypogonadism; and 3 (4.4%) with both GHD and hypogonadism. Subjects with HD had lower mean scores on the IIEF survey (p=0.016) and trended toward lower scores on the SF-36 MCS (p=0.113). MetS was present in 50% of subjects, including 5 of 6 (83%) with hypogonadism, and 29 of 62 (46.8%) without hypogonadism (p=0.087). Age, BMI, median years in NFL, games played, number of concussions, and acknowledged use of performance-enhancing steroids were similar between HD and non-HD groups. In summary, in this cohort of retired NFL players with poor QoL, 23.5% had HD, including 19% with GHD (using a BMI-adjusted definition), 9% with hypogonadism, and 50% had MetS. Although the cause of HD is unclear, these results suggest that GHD and hypogonadism may contribute to poor QoL, erectile dysfunction, and MetS in this population. Further study of pituitary function is warranted in athletes sustaining repetitive mTBI.

Auxology-based cut-off values for biochemical testing of GH secretion in childhood

ObjectiveThe diagnosis of GH deficiency (GHD) in childhood requires GH tests with arbitrary cut-offs. We aimed to define GH cut-offs based on auxology. DesignFrom a total of 349 children diagnosed with GHD between 1985 and 2005 at our hospital, we excluded all children who had additional characteristics likely to interfere with growth velocity. Age at start of therapy was defined as 4 to 8/9years (girls/boys). Auxological inclusion criteria were pathological growth velocity, height at start of therapy >1.5 SD below the target, and efficient catch-up growth during GH therapy. Basal IGF-I/IGFBP-3, GH response to arginine and spontaneous GH secretion at night had been measured by the same polyclonal RIA. The reference was a group of 108 normally growing age-matched children with Turner syndrome or born small for gestational age tested during the same time period. ResultsWe identified 52 children with GHD who fulfilled the inclusion criteria. ROC analysis showed the best diagnostic accuracy at a peak GH cut-off for arginine of 6.6μg/L (sensitivity, 84.3%; specificity, 75.5%; AUC=0.83) and at a peak GH cut-off during spontaneous secretion at night of 7.3μg/L (sensitivity, 96.8%; specificity, 82.4%; AUC=0.93). Our arbitrarily defined GH cut-offs had been higher. Children diagnosed with GHD in the past with GH test values above the new cut-offs were less responsive to GH therapy (P=0.007). ConclusionsHere we provide a new rational approach which allows the substitution of arbitrarily defined GH cut-offs by those based on auxology.

Impact of different cut-off limits of peak GH after GHRH-arginine stimulatory test, single IGF1 measurement, or their combination in identifying adult patients with GH deficiency

To evaluate the impact of different peak GH cut-off limits after GHRH-Arg test, IGF1 measurement, or their combination in identifying patients with GH deficit (GHD). Totally, 894 normal subjects (used for determining IGF1 normative limits) and 302 patients with suspected GHD were included. Different peak GH cut-off limits (used by European (depending on body mass index (BMI)) or North American (4.1 μg/l) Endocrine Societies, by HypoCCs (2.5 μg/l), or with 95% specificity (based on BMI), Method 1, 2, 3, or 4 respectively) and IGF1 were considered. Peak GH after GHRH-Arg and IGF1. Different peak GH cut-off limits recognized different proportions of GHD (range, 24.8-62.9%). Methods 1 and 2 with high sensitivity recognized a higher proportion (95.5 and 92.5% respectively) of GHD among patients with three (T) pituitary hormone deficits (HD), whereas Method 4 (with high specificity) identified 96.7% normal subjects among those without pituitary HD; on the contrary, Method 4 identified only 75% GHD among patients with THD, whereas Method 1 recognized a high proportion (40%) of GHD among subjects without HD. Of the total patients, 82% with THD and 84.5% without HD were recognized as GHD or normal respectively by IGF1. Among the remaining patients with THD and normal IGF1, 75% was recognized as GHD by Method 1; among patients without HD and abnormal IGF1, 87.5% was identified as normal by Method 4. Overall, combination of IGF1 and Method 1 or Method 4 identified 95.5% GHD among patients with THD and 98.1% normal subjects among those without HD. Single peak GH cut-offs have limits to sharply differentiate GHD from normal subjects; IGF1 may be used for selecting patients to be submitted to the GHRH-Arg test; the peak GH cut-off limits to be used for identifying healthy or diseased patients depend mainly on the clinical context.

Effect of Body Mass Index on Peak Growth Hormone Response to Provocative Testing in Children with Short Stature

Obesity is associated with decreased spontaneous and stimulated GH secretion, but the effect of body mass index (BMI) on results of GH stimulation testing in children with short stature is not known. The aim of the study was to determine the impact of BMI on peak GH to provocative testing in children with short stature. This was a retrospective review of provocative GH testing performed in 116 children 2-18 yr old in the ambulatory clinic of the Pediatric Endocrinology Unit at the Massachusetts General Hospital from 2004-2008. The main outcome measure was peak stimulated GH. Height, weight, IGF-I, and IGF-binding protein 3 were also measured. In univariate regression analysis, BMI sd score (BMI SDS) was inversely associated with natural log (ln) peak GH to provocative testing (P = 0.002), whereas height SDS, ln IGF-I, and IGF-binding protein 3 were not significantly associated with ln peak GH. After controlling for age, gender, BMI, and pubertal status, BMI (P = 0.002) remained independently associated with ln peak GH. BMI SDS significantly influenced the likelihood of diagnosis of GH deficiency using peak GH cutoffs of 10, 7, and 5 microg/liter. In children with short stature, BMI affects peak stimulated GH and should be considered when interpreting GH testing. Higher BMI SDS, even within the normal range, may lead to overdiagnosis of GH deficiency.

Reassessment of the Growth Hormone Status in Young Adults with Childhood-Onset Growth Hormone Deficiency: Reappraisal of Insulin Tolerance Testing

The 2007 Consensus Statement suggested a peak GH cutoff to insulin tolerance test (ITT) of less than 6 microg/liter in the diagnosis of permanent GH deficiency (GHD) in young adults with childhood-onset GHD (COGHD), although further validation was recommended. The aim of the study was to evaluate the accuracy of ITT, mean 12-h spontaneous nocturnal GH (SNGH), and IGF-I in the definition of permanent GHD. The study was conducted in two Pediatric Endocrinology Centers. ITT, 12-h SNGH, and IGF-I were evaluated as single or combined tests in 79 subjects with COGHD (median age, 18.0 yr). The cohort consisted of 48 subjects with isolated GHD or one additional pituitary defect and normal MRI or anterior pituitary hypoplasia (group LLGHD, low likelihood GHD), and 31 subjects with structural hypothalamic-pituitary abnormalities or multiple pituitary hormone deficiencies (group HLGHD, high likelihood GHD). Receiver operating characteristic analysis showed the best diagnostic accuracy for peak GH cutoffs to ITT of 5.62 microg/liter or less [sensitivity, 77.4%; specificity, 93.8%; area under the curve (AUC) = 0.92], mean 12-h SNGH of 1.20 microg/liter or less (sensitivity, 90.3%; specificity, 89.6%; AUC = 0.93), and IGF-I of -2.83 sd score or less (sensitivity, 80.7%; specificity, 95.7%; AUC = 0.93). Seven patients in group HLGHD showed a peak GH to ITT above 5.62 microg/liter, but a median IGF-I that was significantly lower than that of group LLGHD (-3.30 vs. -0.73 sd score; P = 0.0001). Peak GH to ITT of 3.6 microg/liter or less and arginine of 3.1 microg/liter or less at childhood diagnosis can predict a future permanent GHD condition. The adopted peak GH to ITT below 5.62 microg/liter is an accurate diagnostic cutoff point for HLGHD in young adults with COGHD. In addition, IGF-I is a reliable marker providing information about the severity of GHD. Careful follow-up is required for subjects with discordant ITT and IGF-I results.

A Reappraisal of Diagnosing GH Deficiency in Adults: Role of Gender, Age, Waist Circumference, and Body Mass Index

The objective of the study was to reevaluate the diagnostic accuracy of GH peak after GHRH plus arginine test (GHRH+ARG) according to patients' age, body mass index (BMI), and waist circumference to diagnose GH deficiency (GHD). GH peak after GHRH+ARG and IGF-I levels reported as sd score. Subjects included 408 controls (218 women, 190 men, aged 15-80 yr) and 374 patients with hypopituitarism (167 women, 207 men, aged 16-83 yr). In the (elderly) healthy subjects 15-25 yr old (young), 26-65 yr old (adults) and older than 65 yr, GH cutoffs were 15.6, 11.7, and 8.5 microg/liter, 11.8, 8.1, and 5.5 microg/liter, and 9.2, 6.1, and 4.0 microg/liter, respectively, in the lean, overweight, and obese subjects. Waist circumference was the best predictor of GH peak (t = -7.6, P < 0.0001) followed by BMI (t = -6.7, P < 0.0001) and age (t = -5.7, P < 0.0001). Based on the old (<9.1 microg/liter) and new GH cutoff, 286 (76.5%) and 276 (73.8%) of 374 hypopituitary patients had severe GHD. The receiving-operator characteristic analysis showed GH cutoffs in line with the third percentile or slightly higher results so that the prevalence of GHD increased to 90.1%. The results of the current study show that waist circumference and BMI are the strongest predictors of GH peak after GHRH+ARG followed by age. However, the old cutoff value of 9.0 microg/liter was in line with the new cutoffs in 95% of patients.

Should We Still Use Glucose-Suppressed Growth Hormone Levels for the Evaluation of Acromegaly?

Acromegaly is associated with increased mortality if not adequately treated (1). Currently accepted biochemical criteria for cure of acromegaly include a mean 24-h GH level less than 2.5 g/liter (5 mU/liter) and/or a glucose-suppressed GH level of less than 1 g/liter (2 mU/liter) and a normal IGF-I (2). These criteria wereproposedbyBatesetal. (3)whoshowedthatpatientswithGH levels less than 2.5 g/liter did not show an increase in mortality. Since l993, this GH cutoff has been widely applied based on the relative paucity of data relating normal IGF-I levels to normal life expectancy. More recently, Holdaway et al. (4) demonstrated that IGF-I (expressed as an SD score) was significantly associated with mortality. Specifically, they showed that patients with last follow-up IGF-I of at least 2 SD had a mortality ratio 3.5 times higher than thosewithan SD score less thanzero (4).Theyalso showed that mortality was 1.6 times higher in patients with last follow-up GH levels less than 2 g/liter, whereas mortality was similar to the control population in patients with last follow-up GH levels less than 1 g/liter, suggesting that cure criteria should be modified, at least for levels of GH. No data are available concerning mortality and the GH nadir after glucose, yet it is included in almost all studies examining the efficacy of treatment in acromegaly. There are several areas of debate related to the value of the GH response to glucose. First, the additional diagnostic value over a fasting GH level is limited when the IGF-I level is elevated (5), and additionally, a similar diagnostic accuracy of a GH profile and nadir GH after glucose was demonstrated in a large series of patients (6). Second, the clinical implication of a single unsuppressed GH level in patients studied after surgery and showing normal serum IGF-I levels and GH levels below the threshold of cured patients is still a matter of discussion. In this setting, Freda et al. (7) showed that patients considered cured after surgery (normal IGF-I and postglucose GH nadir 0.14 g/liter) did not demonstrate recurrence of acromegaly in long-term follow-up. These data suggest a very relevant role for assessment of GH after glucose to detect patients with a likelihood for recurrence, which is clearly an important clinical outcome. The threshold GH nadir of no more than 0.14 g/liter is, however, well below that mentioned in the 2000 consensus criteria for cured acromegaly (2); the lower threshold was justified by using a highly sensitive GH assay able to detect levels as low as 0.05 g/liter. Lower nadir GH values of 0.25 and 0.26 g/liter after glucose, also using a highly sensitive GH assay, were reported by Costa et al. (8) and Gullu et al. (9), respectively. Thus, the question as to which GH cutoff value should be used for postglucose GH nadir immediately rises. The assay sensitivity is a crucial aspect of diagnostic accuracy of any biochemical test. It is now known that previously used polyclonal RIAs for GH were insufficiently sensitive to discriminate GH levels around 2 g/liter (5). Modern immunoradiometric assays for GH have a detection limit of 0.05 g/liter, so the ability to discriminate postglucose GH levels in patients with active acromegaly vs. healthy subjects is improved. In this issue of the Journal, Arafat et al. (10) have compared different assays to address further the issue of the appropriate GH nadir after glucose currently used in the treatment evaluation of acromegaly. They measured GH after 75 g glucose in 46 acromegaly patients, 18 with controlled disease and 28 with uncontrolled disease, and in 213 healthy subjects using three commercially available assays (Immulite, Nichols, and DSL) that were calibrated against therecentlyrecommendedGHstandards.Asexpected, their results showed that GH levels measured with all assays were stronglycorrelated(rvalues0.8–0.996)Importantly,however,GH levels assessed with the Immulite assay were, on average, 2.3-fold higher than thoseobtainedwith theNichols assayand6-foldhigher than those obtained with the DSL assay (10). Therefore, in centers where Immulite is thestandardmethod, the likelihoodthatapatient with normal IGF-I will have a discrepant unsuppressed GH after glucose is higher than in centers using other methods. To provide clinical advice, the authors propose that a cutoff GH level of 1 g/liter be used with the Immulite method and 0.5 g/liter with the Nichols method; this allowed the authors to identify 95% of patients with active disease and 78–80% of patients in remission.

Relationship between Disease-Related Morbidity and Biochemical Markers of Activity in Patients with Acromegaly

The criteria for biochemical control of acromegaly that will best reduce disease-related morbidity in acromegaly are debated. We therefore studied the relationship of biochemical markers with an important metabolic parameter, insulin sensitivity, and clinical parameters reflecting disease activity in acromegaly. Newly diagnosed and postoperative patients with acromegaly underwent assessment of fasting IGF-I and fasting and postoral glucose tolerance test GH and insulin levels and completed a numeric signs and symptoms questionnaire. Insulin sensitivity was estimated by the quantitative insulin sensitivity check index (QUICKI) and the composite insulin sensitivity index. Patients were divided into three groups: group I, normal IGF-I and nadir GH less than 0.14 mug/liter (n = 21); group II, normal IGF-I and nadir GH 0.14 mug/liter or more (n = 20); group III (active), elevated IGF-I (n = 25). Age, sex, and body mass index were comparable in these groups. Insulin sensitivity was reduced in group III (QUICKI: 0.33 +/- 0.01 and composite index: 3.44 +/- 0.54), compared with group II (0.38 +/- 0.01, P = 0.002 and 8.18 +/- 1.21, P = 0.0008), group I (0.38 +/- 0.01, P = 0.0008 and 8.91 +/- 1.34, P = 0.00001), and healthy controls (0.37 +/- 0.008, P = 0.009). When other nadir GH cut-offs were analyzed, insulin sensitivity remained relatively reduced in the elevated IGF-I group. IGF-I was a significant predictor for decreasing insulin sensitivity as calculated by QUICKI (r = 0.6, P < 0.0001) independently of nadir GH. Signs and symptom scores were higher in group III (mean 38.5 +/- 3.6%), compared with group II (mean 23.5 +/- 3.2%, P = 0.004) and group I (mean 20.5 +/- 3.7%, P = 0.0008) but not between the latter two groups. Our data indicate that overall and specifically in the presence of discordant serum IGF-I and nadir GH levels, IGF-I was more predictive than GH levels of insulin sensitivity and clinical symptom score in patients with acromegaly.