In humans, serum growth hormone (GH) concentrations are significantly higher in women than in men, but the neuroendocrine mechanisms that underlie such gender differences are not known. We compared normal episodic GH secretion in males and females in three distinct settings: two human studies employing quite different assay techniques (immunoradiometric assay and a high-sensitivity immunofluorimetric method) and a rat study. To quantify the amount of regularity in data, we utilized approximate entropy (ApEn), a scale- and model-independent statistic. In each study, females exhibited significantly greater statistical irregularity in GH concentration series than their male counterparts (P < 10(-3) for each human study, P < 10(-6) for the rat study), implying that mass and mode of GH secretion are regulated differently in males and females. The regularity comparisons indicated complete gender separation (100% specificity and sensitivity) for the rat study and nearly complete separation for the immunofluorimetric assay study. The consistency and statistical significance of these findings suggest that this gender difference may be broadly based within higher animals and that this may be readily evaluated objectively by analysis of ApEn.

Although the use of the insulin tolerance test (ITT) for the diagnosis of adult GH deficiency is well established, diagnostic peak GH cut-points for other commonly used GH stimulation tests are less clearly established. Despite that fact, the majority of patients in the United States who are evaluated for GH deficiency do not undergo insulin tolerance testing. The aim of this study was to evaluate the relative utility of six different methods of testing for adult GH deficiency currently used in practice in the United States and to develop diagnostic cut-points for each of these tests. Thirty-nine patients (26 male, 13 female) with adult-onset hypothalamic-pituitary disease and multiple pituitary hormone deficiencies were studied in comparison with age-, sex-, estrogen status-, and body mass index-matched control subjects (n ‫؍‬ 34; 20 male, 14 female). A third group of patients (n ‫؍‬ 21) with adult-onset hypothalamic-pituitary disease and no more than one additional pituitary hormone deficiency was also studied. The primary end-point was peak serum GH response to five GH stimulation tests administered in random order at five separate visits: ITT, arginine (ARG), levodopa (L-DOPA), ARG plus L-DOPA, and ARG plus GHRH. Serum IGF-I concentrations were also measured on two occasions. For purposes of analysis, patients with multiple pituitary hormone deficiencies were assumed to be GH deficient. Three diagnostic cut-points were calculated for each test to provide optimal separation of multiple pituitary hormone deficient and control subjects according to three criteria: 1) to minimize misclassification of control subjects and deficient patients (balance between high sensitivity and high specificity); 2) to provide 95% sensitivity for GH deficiency; and 3) to provide 95% specificity for GH deficiency. The greatest diagnostic accuracy occurred with the ITT and the ARG plus GHRH test, although patients preferred the latter (P ‫؍‬ 0.001). Using peak serum GH cut-points of 5.1 g/liter for the ITT and 4.1 g/liter for the ARG plus GHRH test, high sensitivity (96 and 95%, respectively) and specificity (92 and 91%, respectively) for GH deficiency were achieved. To obtain 95% specificity, the peak serum GH cutpoints were lower at 3.3 g/liter and 1.5 g/liter for the ITT and ARG plus GHRH test, respectively. There was substantial overlap between patients and control subjects for the ARG plus L-DOPA, ARG, and L-DOPA tests, but test-specific cutpoints could be defined for all three tests to provide 95% sensitivity for GH deficiency (peak GH cut-points: 1.5, 1.4 and 0.64 g/liter, respectively). However, 95% specificity could be achieved with the ARG plus L-DOPA and ARG tests only with very low peak GH cut-points (0.25 and 0.21 g/liter, respectively) and not at all with the L-DOPA test. Although serum IGF-I levels provided less diagnostic discrimination than all five GH stimulation tests, a value below 77.2 g/liter was 95% specific for GH deficiency. In conclusion, the diagnosis of adult GH deficiency can be made without performing ...

Pulses of growth hormone (GH) release in acromegaly may arise from hypothalamic regulation or from random events intrinsic to adenomatous tissue. To distinguish between these possibilities, serum GH concentrations were measured at 5-min intervals for 24 h in acromegalic men and women with active (n = 19) and inactive (n = 9) disease and in normal young adults in the fed (n = 20) and fasted (n = 16) states. Daily GH secretion rates, calculated by deconvolution analysis, were greater in patients with active acromegaly than in fed (P < 0.05) but not fasted normal subjects. Significant basal (nonpulsatile) GH secretion was present in virtually all active acromegalics but not those in remission or in fed and fasted normal subjects. A recently introduced scale-and model-independent statistic, approximate entropy (ApEn), was used to test for regularity (orderliness) in the GH data. All but one acromegalic had ApEn values greater than the absolute range in normal subjects, indicating reduced orderliness of GH release; ApEn distinguished acromegalic from normal GH secretion (fed, P < 1012; fasted, P < 10-') with high sensitivity (95%) and specificity (100%).Acromegalics in remission had ApEn scores larger than those of normal subjects (P < 0.0001) but smaller than those of active acromegalics (P < 0.001). The coefficient of variation of successive incremental changes in GH concentrations was significantly lower in acromegalics than in normal subjects (P < 0.001). Fourier analysis in acromegalics revealed reduced fractional amplitudes compared to normal subjects (P < 0.05). We conclude that GH secretion in acromegaly is highly irregular with disorderly release accompanying significant basal secretion. (J. Clin. Invest. 1994. 94:1277

Adult GH deficiency (GHD) is currently diagnosed in patients with either a history of childhood-onset GHD or acquired hypothalamic-pituitary disease by GH stimulation testing. However, GH stimulation tests are invasive, time consuming, and associated with side effects. Based on preliminary analyses of patients enrolled in the U.S. Hypopituitary Control and Complications Study (HypoCCS), we proposed the presence of adult GHD could be predicted with 95% accuracy by the presence of three or more pituitary hormone deficiencies (PHDs) or a serum IGF-I concentration less than 84 microg/liter (11 nmol/liter). To validate the diagnostic utility of these criteria, we studied results obtained in 817 adult patients (mean [SD] age: 46.4 [15.7] yr, body mass index: 30.1 [7.2] kg/m(2)) enrolled in HypoCCS who had serum GH concentrations from stimulation tests (11 different tests used, excluding clonidine) and serum IGF-I (competitive binding RIA) measured at the central laboratory (Esoterix Endocrinology, Calabasas Hills, CA). When patients were stratified into subgroups on the basis of the presence of zero, one, two, three, and four additional PHDs, median (25th, 75th percentile) peak GH levels (micrograms per liter) were 3.5 (0.85, 7.1), 0.73 (0.18, 4.2), 0.29 (0.05, 1.4), 0.06 (0.025, 0.295), and 0.025 (0.025, 0.07), respectively. The mean log (peak GH) concentration was significantly different among the subgroups (P < 0.05). The proportion of patients in each group with severe GHD diagnosed by stimulation testing (peak GH < 2.5 microg/liter) was 41%, 67%, 83%, 96%, and 99% for patients with zero, one, two, three, and four PHDs, respectively. The positive predictive values (PPVs) for GHD of three PHDs, four PHDs, and serum IGF-I less than 84 microg/liter were 96%, 99%, and 96%, respectively. The PPV of these three diagnostic criteria was also 95% or more after excluding the data originally used to identify these potential predictors. Taken together, the presence of either three or four additional PHDs or IGF-I less than 84 microg/liter (55% of the patients met at least one of these criteria) reliably predicted GHD with a high PPV (95%), high specificity (89%), and moderate sensitivity (69%). We concluded that patients with an appropriate clinical history and either the presence of three or four additional PHDs or serum IGF-I less than 84 microg/liter (measured in the Esoterix assay) do not require GH stimulation testing for the diagnosis of adult GHD. In clinical practice, we suggest that other causes of low serum IGF-I should be excluded before applying these diagnostic criteria.

We investigated non-alcoholic fatty liver disease (NAFLD) prevalence and its metabolic associations in patients with type 1 diabetes (T1D), and in insulin-naïve and insulin-treated patients with type 2 diabetes (T2D). Baseline data from patients who had liver fat content (LFC) evaluated by magnetic resonance imaging in four phase 3 studies of basal insulin peglispro (BIL) were analysed. Associations of NAFLD with clinical characteristics, glycaemic control and diabetes therapy were evaluated. The prevalence of NAFLD (defined as LFC ≥ 6%) was low in T1D (8.8%) but high in T2D, with greater prevalence in insulin-naïve (75.6%) vs insulin-treated (61.7%) T2D patients. LFC (mean ± SD) was higher in T2D patients (insulin-naïve, 13.0% ± 8.4%; insulin-treated, 10.2% ± 7.8%) than in T1D patients (3.2% ± 3.2%). In T2D, NAFLD was associated with several markers of insulin resistance. In all three populations, there was an absence of association of HbA1c with LFC, but insulin doses were higher in patients with NAFLD.

To determine the effect of tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptors, on biomarkers of nonalcoholic steatohepatitis (NASH) and fibrosis in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODSPatients with T2DM received either once weekly tirzepatide (1, 5, 10, or 15 mg), dulaglutide (1.5 mg), or placebo for 26 weeks. Changes from baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST), keratin-18 (K-18), procollagen III (Pro-C3), and adiponectin were analyzed in a modified intentionto-treat population. RESULTSSignificant (P < 0.05) reductions from baseline in ALT (all groups), AST (all groups except tirzepatide 10 mg), K-18 (tirzepatide 5, 10, 15 mg), and Pro-C3 (tirzepatide 15 mg) were observed at 26 weeks. Decreases with tirzepatide were significant compared with placebo for K-18 (10 mg) and Pro-C3 (15 mg) and with dulaglutide for ALT (10, 15 mg). Adiponectin significantly increased from baseline with tirzepatide compared with placebo (10, 15 mg). CONCLUSIONSIn post hoc analyses, higher tirzepatide doses significantly decreased NASH-related biomarkers and increased adiponectin in patients with T2DM.The prevalence of nonalcoholic fatty liver disease (NAFLD) is ;25% globally and ;60-75% in patients with type 2 diabetes mellitus (T2DM) (1,2). Nonalcoholic steatohepatitis (NASH) (NAFLD with inflammation and hepatocyte injury, with or without fibrosis) can progress to cirrhosis, liver failure, hepatocellular carcinoma, and increased cardiovascular risk (3,4). T2DM increases the risk of NASH twofold (5). Weight loss through lifestyle modification reduces liver fat; weight reductions $10% can induce NASH resolution in most patients (6).Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) promote weight loss and may have efficacy in NASH (7). Tirzepatide, a 39-amino acid synthetic peptide, has agonist activity at both glucose-dependent insulinotropic polypeptide (GIP) and GLP-1

To investigate the effects of exercise intensity on growth hormone (GH) release, 10 male subjects were tested on 6 randomly ordered occasions [1 control condition (C), 5 exercise conditions (Ex)]. Serum GH concentrations were measured in samples obtained at 10-min intervals between 0700 and 0900 (baseline) and 0900 and 1300 (exercise+ recovery). Integrated GH concentrations (IGHC) were calculated by trapezoidal reconstruction. During Ex subjects exercised for 30 min (0900-0930) at one of the following intensities [normalized to the lactate threshold (LT)]: 25 and 75% of the difference between LT and rest (0.25LT and 0.75LT, respectively), at LT, and at 25 and 75% of the difference between LT and peak (1.25LT and 1.75LT, respectively). No differences were observed among conditions for baseline IGHC. Exercise+recovery IGHC (mean +/- SE: C = 250 +/- 60; 0.25LT = 203 +/- 69; 0.75LT = 448 +/- 125; LT = 452 +/- 119; 1.25LT = 512 +/- 121; 1.75LT = 713 +/- 115 microg x l(-1) x min(-1)) increased linearly with increasing exercise intensity (P < 0.05). Deconvolution analysis revealed that increasing exercise intensity resulted in a linear increase in the mass of GH secreted per pulse and GH production rate [production rate increased from 16. 5 +/- 4.5 (C) to 32.1 +/- 5.2 microg x distribution volume(-1) x min(-1) (1.75LT), P < 0.05], with no changes in GH pulse frequency or half-life of elimination. We conclude that the GH secretory response to exercise is related to exercise intensity in a linear dose-response pattern in young men.

We examined the validity of percent body fat (%Fat) estimation by two-compartment (2-Comp) hydrostatic weighing (Siri 2-Comp), 3-Comp dual-energy X-ray absorptiometry (DEXA 3-Comp), 3-Comp hydrostatic weighing corrected for the total body water (Siri 3-Comp), and anthropometric methods in young and older individuals (n = 78). A 4-Comp model of body composition served as the criterion measure of %Fat (Heymsfield 4-Comp; S. B. Heymsfield, S. Lichtman, R. N. Baumgartner, J. Wang, Y. Kamen, A. Aliprantis, and R. N. Pierson Jr., Am. J. Clin. Nutr. 52: 52-58, 1990.). Comparison of the Siri 3-Comp with the Heymsfield 4-Comp model revealed mean differences of /= r = 0.997, total error values