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M O Thorner

Publications and source records attributed to M O Thorner.

At least 37 records · Page 2Linked to original sources
PubMed1999

Validity of methods of body composition assessment in young and older men and women.

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 </=0.4 %Fat, r values >/= r = 0.997, total error values </= 0.85 %Fat, and 95% confidence intervals (Bland-Altman analysis) of </=1.7 %Fat. Comparison of Siri 2-Comp, DEXA, and anthropometric models with the Heymsfield 4-Comp revealed that total error scores ranged from +/-4. 0 to +/-10.7 %Fat, and 95% confidence intervals associated with the Bland-Altman analysis ranged from +/-5.1 to +/-15.0 %Fat. We conclude that the Siri 3-Comp model provides valid and accurate body composition data when compared with a 4-Comp criterion model. However, the individual variability associated with the Siri 2-Comp, DEXA 3-Comp, and anthropometric models may limit their use in research settings. The use of anthropometric estimation methods resulted in large mean differences and a considerable amount of interindividual variability. These data suggest that the use of these techniques should be viewed with caution.

Absorptiometry, Photon↗
PubMed1999

The mutant growth hormone-releasing hormone (GHRH) receptor of the little mouse does not bind GHRH.

The little mouse is a dwarf strain characterized by low levels of GH, pituitary hypoplasia, and an unresponsiveness to treatment with exogenous GHRH. The defect has been mapped to a missense mutation in the GHRH receptor gene that abolishes the function of the receptor, but the mechanism of this inactivation is unknown. Receptor function might be affected at the level of protein expression, maturation and processing, localization to the cell surface, ligand binding, or signaling. In this study, Western blots, using antiserum raised against the GHRH receptor and immunoprecipitation analysis of epitope-tagged receptors, demonstrate that both wild-type and mutant receptor proteins are expressed at equivalent levels in transfected cells. Immunofluorescence analysis of intact and permeabilized cells expressing the epitope-tagged receptors suggests that wild-type and little mouse receptors are similarly localized to the cell surface. A species homologous binding assay was developed and used to show that 125I-mouse GHRH binds with high affinity to the wild-type mouse receptor but not to the little mutant receptor. Consistent with this, the mutant receptor fails to stimulate intracellular cAMP accumulation. Our results demonstrate that the little mutation does not dramatically affect the expression level, glycosylation, or cellular localization of the receptor protein but that it blocks specific GHRH binding, and therefore, signaling does not take place.

Amino Acid Sequence↗
PubMed1999

Growth hormone (GH) receptor blockade with a PEG-modified GH (B2036-PEG) lowers serum insulin-like growth factor-I but does not acutely stimulate serum GH.

B2036-PEG, a GH receptor (GH-R) antagonist, is an analog of GH that is PEG-modified to prolong its action. Nine mutations alter the binding properties of this molecule, preventing GH-R dimerization and GH action. A potential therapeutic role of B2036-PEG is to block GH action, e.g. in refractory acromegaly. A phase I, placebo-controlled, single rising-dose study was performed in 36 normal young men (ages, 18-37 yr; within 15% ideal body weight). Four groups received a single s.c. injection of either placebo (n = 3 in each group, total n = 12) or B2036-PEG (0.03, 0.1, 0.3, or 1.0 mg/kg; n = 6 each dose). B2036-PEG and GH concentrations were measured 0, 0.25, 0.5, 1, 3, 6, 9, 12, 24, 36, 48, 72, 96, 120, and 144 h after dosing. Serum insulin-like growth factor-I was measured before and 1-7 days after dosing. All doses were well tolerated, with no serious or severe adverse reactions. B2036-PEG, at 1.0 mg/kg, reduced insulin-like growth factor-I by 49 +/- 6% on day 5 (P < 0.001 vs. placebo). GH was measured by two independent methods: 1) modified Nichols chemiluminescence assay (empirically corrected for B2036-PEG cross-reactivity); and 2) direct GH two-site immunoassay, using monoclonal antibodies that did not react with B2036-PEG. There was good agreement between the two methods. GH did not change substantially at any B2036-PEG dose, suggesting that B2036-PEG does not interact with hypothalamic GH-Rs to block short-loop feedback. B2036-PEG may thus block peripheral GH action without enhancing its secretion.

Adolescent↗
PubMed1998

The diagnosis of severe growth hormone deficiency in elderly patients with hypothalamic-pituitary disease.

OBJECTIVE: Adults over the age of 60 years with organic disease of the hypothalamic-pituitary axis may be deficient in growth hormone (GH) to a degree that is distinct from the age-related decline in GH secretion and sufficient to cause perturbations of body composition, serum lipid profile and bone metabolism. In order to determine the best method for detecting GH deficiency in this age group we have compared spontaneous GH secretion, a provocative test of GH secretion, the arginine stimulation test (AST), and basal estimates of circulating insulin-like growth factors (IGF) and IGF-binding proteins (IGFBP). DESIGN: Twenty-four patients (16 male) with organic hypothalamic-pituitary disease and 24 controls (17 male) were studied. The groups were matched for BMI but the patients were slightly younger than the controls, 66.0 (61.0-85.7) vs. 70.6 (60.8-87.5) years (P = 0.04). All subjects underwent a 24-h GH profile (20-minute sampling), measurement of serum IGF-I, IGF-II, IGFBP3, IGFBP2 and growth hormone binding protein (GHBP) and, after an overnight fast, an AST (intravenous arginine 20 g/m2 over 30 minutes). GH concentrations were measured using an ultrasensitive chemiluminescence assay (sensitivity 0.002 microgram/l). Normative data for serum IGF-I, IGF-II, IGFBP3 and IGFBP2 were obtained from 125 subjects aged 60-87 years. RESULTS: None of the parameters studied was able to distinguish between all the GH deficient patients and the healthy controls. The median (range) area under the GH profile (AUCGH) and peak GH response to arginine were lower in the patients than in the controls, 310.05 (18.90-2193.36) vs. 2518.20 (526.76-12024.97) min mU/l (P < 0.00001), 1.07 (0.08-17.90) vs. 23.06 (4.60-109.98) mU/l (P < 0.00001), respectively. There was a significant relationship between AUCGH and peak GH response to arginine in the patients (r = 0.89, P < 0.0001) and in the controls (r = 0.56, P = 0.005). Serum IGF-I, IGFBP2, and IGFBP3 levels were significantly lower in the patients compared with the normal range, 102 (14-162) vs. 142 (59-298) micrograms/l (P < 0.0001), 415 (122-1868) vs. 640 (140-2585) micrograms/l (P = 0.0007) and 2.29 (0.81-3.75) vs. 2.59 (1.00-3.52) mg/l (P = 0.009), respectively. The degree of overlap between the two groups, however, was too great to make these measurements useful diagnostically. Serum IGF-II and GHBP concentrations in the patients were not significantly different from the normal range. The patients were divided into groups determined by the number of anterior pituitary hormone deficits present. There was a significant downward trend in the peak GH response to arginine with increasing severity of hypopituitarism (J = -3.04, P = 0.0012). Ninety per cent of patients with two or three additional pituitary deficiencies had a peak GH response less than 2.0 mU/l. CONCLUSIONS: Of the indices studied the arginine stimulation test is more effective than GH markers, such as IGF-I or IGFBP3, or measurement of spontaneous GH secretion for diagnosing GH deficiency in adults over the age of 60 years. By relating the peak GH response to the degree of hypopituitarism, a GH response less than 2.0 mU/l is suggestive of severe GH deficiency in this age group under the appropriate clinical circumstances.

Aged↗
PubMed1998

Evidence against a role for the growth hormone-releasing peptide axis in human slow-wave sleep regulation.

A complex interrelationship exists between sleep and somatotropic activity. In humans, intravenous injections of growth hormone-releasing hormone (GHRH) given during sleep consistently stimulate slow-wave (SW) sleep, particularly when given in the latter part of the night. In the present study, the possible somnogenic effects induced under similar conditions by GH-releasing peptide (GHRP) were investigated in seven young healthy men. Bolus intravenous injections of GHRP-2 (1 microgram/kg body wt) or saline, in randomized order, were given after 60 s of the third rapid-eye-movement period. All GHRP injections were immediately followed by transient prolactin elevations and by GH pulses of a magnitude within or around the upper limit of the physiological range. Except for a nonsignificant tendency to increased amounts of wakefulness during the 1st h after the injection, no effects of GHRP-2 administration on sleep were detected. There was in particular no enhancement of SW sleep. Thus, in contrast to GHRH, late-night single injections of GHRP-2 at a dosage resulting in similar GH elevations have no stimulatory effects on SW sleep. The present data provide evidence against the involvement of the GHRP axis in human SW sleep regulation.

Adult↗
PubMed1998

Growth hormone secretagogue receptor expression in human pituitary tumors.

The GH secretagogue (GHS) receptor (GHS-R) has been characterized and cloned. It is a member of a family of seven transmembrane receptors and is closely related to the neurotensin and TRH receptors. To determine the expression of this receptor in normal anterior pituitary and in 24 human pituitary adenomas, we analyzed GHS-R messenger ribonucleic acid (mRNA) using a RT-PCR assay. We found that normal human pituitary was positive for the GHS-R signal. In addition, all GH-secreting adenomas and the one TSH-secreting adenoma demonstrated the presence of GHS-R mRNA. Three of four ACTH-secreting tumors and three of nine gonadotroph adenomas were also positive for the GHS-R mRNA. To determine the amounts of GHS-R mRNA in normal pituitary and in representative tumors, semiquantitative competitive PCR was performed. We determined that normal pituitary had approximately 750 molecules/L GHS-R mRNA. The acromegalic tumor had approximately 1.5 x 10(5) molecules/L, and the TSH-secreting tumor had approximately 7.5 x 10(3) molecules/L. Other tumor types contained considerably less, with the ACTH-secreting and gonadotroph tumors expressing 7.5 x 10(2) and 3 x 10(2) GHS-R mRNA molecules/L, respectively. These results suggest that GH- and TSH-producing adenomas express GHS-R mRNA at levels 200 and 10 times higher, respectively, than the normal pituitary, and that this receptor expression may be involved in the pathogenesis and growth of these pituitary adenomas.

Adenoma↗
PubMed1998

Urinary growth hormone (GH), insulin-like growth factor I (IGF-I), and IGF-binding protein-3 measurements in the diagnosis of adult GH deficiency.

The diagnosis of GH deficiency (GHD) in the elderly is based at present on the peak GH concentration during a stimulation test. We have now evaluated the performance of urinary GH (uGH), urinary insulin-like growth factor I (uIGF-I), and urinary IGF-binding protein-3 (uIGFBP-3) in the diagnosis of GHD in this group. Twenty GHD elderly patients with a history of pituitary disease and a peak GH response to arginine stimulation of less than 3 ng/mL (15 men and 5 women; age, 61.1-83.4 yr) and 19 controls (12 men and 7 women; age, 60.8-87.5 yr) were studied. GH secretion was assessed by 24-h profile and expressed as the area under the curve (AUCGH). Serum (s) IGF-I and sIGFBP-3 were measured in a single morning, fasted sample. Urinary GH, uIGF-I, and uIGFBP-3 were measured in a 24-h urine sample collected over the same interval as the GH profile, and results were expressed as total amount excreted in 24 h (tuGH24, nanograms; tuIGF-I24, nanograms; tuIGFBP-3(24), micrograms). Data are presented as the mean +/- SD, except for AUCGH, tuGH24, and tuIGFBP-3(24), which are presented as the geometric mean (-1, +1 tolerance factor). AUCGH, sIGF-I, and sIGFBP-3 were significantly lower in GHD subjects than in controls. Total uGH24 was lower in GHD subjects, but tuIGF-I24 and tuIGFBP-3(24) excretion were not different in the two groups. AUCGH provided the best separation between GHD and control subjects, whereas there was substantial overlap for sIGF-I, sIGFBP-3, and tuGH24. In both groups sIGF-I was correlated to sIGFBP-3 (GHD, r = 0.75; controls, r = 0.65; both P < 0.01), whereas tuIGF-I24 was not correlated to tuIGFBP-3(24) in either group. Moreover, tuIGF-I24 and tuIGFBP-3(24) were not related to their respective serum concentrations in either group. Total uGH24 was correlated with AUCGH only in controls (r = 0.54; P < 0.05). These data demonstrate that urinary GH and urinary and serum IGF-I and IGFBP-3 are not suitable diagnostic markers for GHD in elderly subjects.

Aged↗
PubMed1998

Recovery of growth hormone release from suppression by exogenous insulin-like growth factor I (IGF-I): evidence for a suppressive action of free rather than bound IGF-I.

To determine the time course of recovery of GH release from insulin-like growth factor I (IGF-I) suppression, 11 healthy adults (18-29 yr) received, in randomized order, 4-h i.v. infusions of recombinant human IGF-I (rhIGF-I; 3 microg/kg-h) or saline (control) from 25.5-29.5 h of a 47.5-h fast. Serum GH was maximally suppressed within 2 h and remained suppressed for 2 h after the rhIGF-I infusion; during this 4-h period, GH concentrations were approximately 25% of control day levels [median (interquartile range), 1.2 (0.4-4.0) vs. 4.8 (2.8-7.9) microg/L; P < 0.05]. A rebound increase in GH concentrations occurred 5-7 h after the end of rhIGF-I infusion [7.6 (4.6 -11.7) vs. 4.3 (2.5-6.0) microg/L; P < 0.05]. Thereafter, serum GH concentrations were similar on both days. Total IGF-I concentrations peaked at the end of the rhIGF-I infusion (432 +/- 43 vs. 263 +/- 44 microg/L; P < 0.0001) and remained elevated 18 h after the rhIGF-I infusion (360 +/- 36 vs. 202 +/- 23 microg/L; P = 0.001). Free IGF-I concentrations were approximately 140% above control day values at the end of the infusion (2.1 +/- 0.4 vs. 0.88 +/- 0.3 microg/L; P = 0.001), but declined to baseline within 2 h after the infusion. The close temporal association between the resolution of GH suppression and the fall of free IGF-I concentrations, and the lack of any association with total IGF-I concentrations suggest that unbound (free), not protein-bound, IGF-I is the major IGF-I component responsible for this suppression. The rebound increase in GH concentrations after the end of rhIGF-I infusion is consistent with cessation of an inhibitory effect of free IGF-I on GH release.

Adolescent↗
PubMed1998

Unequal impact of age, percentage body fat, and serum testosterone concentrations on the somatotrophic, IGF-I, and IGF-binding protein responses to a three-day intravenous growth hormone-releasing hormone pulsatile infusion in men.

We here investigate the potential rescue of the relative hyposomatotropism of aging and obesity by 3-day pulsatile GHRH infusions (i.v. bolus 0.33 microg/kg every 90 min) in 19 healthy men of varying ages (18 to 66 years) and body compositions (12 to 37% total body fat). Baseline (control) and GHRH-driven pulsatile GH secretion (in randomly ordered sessions) were quantitated by deconvolution analysis of 24-h (10-min sampling) serum GH concentration profiles measured in an ultrasensitive (threshold 0.005 microg/l) chemiluminescence assay. GHRH infusion significantly increased the mean (24-h) serum GH concentration (0.3 +/- 0.1 basal vs 2.4 +/- 0.4 microg/l treatment; P = 0.0001), total daily pulsatile GH production rate (21 +/- 9.5 vs 97 +/- 17 microg/l/day; P = 0.01), GH secretory burst frequency (11 +/- 0.5 vs 17 +/- 0.3 events/day; P = <0.01), and mass of GH released per burst (1.1 +/- 0.4 vs 5.9 1 microg/l; P < 0.01), as well as serum IGF-I (261 +/- 33 vs 436 +/- 37 microg/l; P = 0.005), insulin (45 +/- 13 vs 79 +/- 17 mU/l; P = 0.0002), and IGF binding protein (IGFBP)-3 (3320 +/- 107 vs 4320 +/- 114 microg/l; P = 0.001) concentrations, while decreasing IGFBP-1 levels (16 +/- 1.2 vs 14 +/- 0.09 microg/l; P = 0.02). Serum total testosterone and estradiol concentrations did not change. GHRH treatment also reduced the half-duration of GH secretory bursts, and increased the GH half-life. GHRH-stimulated 24-h serum GH concentrations and the mass of GH secreted per burst were correlated negatively with age (R[value]:P[value] = -0.67:0.002 and -0.58:0.009 respectively), and percentage body fat (R:P = -0.80:0.0001 and -0.65:0.0005 respectively), but positively with serum testosterone concentrations (R:P = +0.55:0.016 and +0.53:0.019 respectively). GHRH-stimulated plasma IGF-I increments correlated negatively with age and body mass index, and positively with serum testosterone, but not with percentage body fat. Cosinor analysis disclosed persistent nyctohemeral rhythmicity of GH secretory burst mass (with significantly increased 24-h amplitude and mesor values) but unchanged acrophase during fixed pulsatile GHRH infusions, which suggests that both GHRH- and non-GHRH-dependent mechanisms can modulate the magnitude (but only non-GHRH mechanisms can modulate the timing) of somatotrope secretory activity differentially over a 24-h period. In summary, diminished GHRH action and/or non-GHRH-dependent mechanisms (e.g. somatostatin excess, putative endogenous growth hormone-releasing peptide deficiency etc.) probably underlie the hyposomatotropism of aging, (relative) obesity, and/or hypoandrogenemia. Preserved or increased tissue IGF-I responses to GHRH-stimulated GH secretion (albeit absolutely reduced, suggesting GHRH insensitivity in obesity) may distinguish the pathophysiology of adiposity-associated hyposomatotropism from that of healthy aging.

Adipose Tissue↗
PubMed1997

The influence of anatomical boundaries, age, and sex on the assessment of abdominal visceral fat.

Single-slice abdominal computed tomography (CT) scanning has been used extensively for the measurement of abdominal visceral fat (AVF). Optimal anatomical scan location and pixel density ranges have been proposed and are specifically reported to allow for the replication and standardization of AVF measurements. Standardization of the anatomical boundaries for CT measurement of AVF and the influence of age and gender on results obtained with different boundary locations have received much less attention. To determine the influence of three boundary analysis methods (AVF-1, AVF-2, and AVF-3) on the measurement of AVF by CT, 54 older (60 years to 79 years) and 37 younger (20 years to 29 years) healthy men and women were examined. The measurement boundary for AVF-1 was the internal most aspect of the abdominal and oblique muscle walls, and the posterior aspect of the vertebral body. AVF-2 used fat measurements enclosed in a boundary formed by the midpoint of the abdominal and oblique muscle walls, and the most posterior aspect of the spinous process. AVF-3 used fat measurements enclosed in a boundary formed by the external border of the abdominal and oblique muscle walls, and the external border of the erector spinae. Greater AVF measures were obtained with AVF-2 and AVF-3 compared with AVF-1 (p < 0.0001). These differences were greater in older compared with younger subjects (p < 0.0001) and greater in women compared with men (p < 0.02). The significantly greater AVF measurements obtained with AVF-2 and AVF-3 resulted from the inclusion of larger amounts of fat that are not drained by the portal circulation. This included retroperitoneal, intermuscular, and intramuscular lipid droplets, which increase with aging. On the basis of these results, we recommend the AVF-1 anatomical boundaries for the measurement of AVF in clinical investigations, particularly with older subjects. These data demonstrate the importance of precise and reproducible anatomical boundaries for the measurement of AVF, particularly in longitudinal studies.

Abdomen↗
PubMed1997

Relationship between growth hormone (GH) status, serum leptin and body composition in healthy and GH deficient elderly subjects.

OBJECTIVE: Growth hormone (GH) secretion declines with age and is affected by body composition. The signal that mediates the latter relationship remains III-defined. Leptin, the protein product of the adipocyte specific ob gene, is thought to accurately reflect fat mass and could therefore be a candidate to influence GH secretion. We have therefore investigated the relationship between GH status, leptin and body composition in normal and GH-deficient elderly subjects. DESIGN: GH Secretion was assessed by 20-minute sampling over 24 hours and serum leptin concentrations were measured in a single morning, fasted sample. PATIENTS: Twenty-one GH deficient elderly patients (61-83 years) and 22 gender- and BMI-matched controls (61-88 years). MEASUREMENTS: Body composition was assessed by dual-energy X-ray absorptiometry (DEXA). GH was measured in an ultrasensitive chemiluminescent assay and serum leptin was determined by radio-immunoassay. RESULTS: Leptin was correlated with percentage body fat in both sexes (male r = 0.75, female r = 0.89, both P < 0.001). Male patients had increased fat mass (FM) (P < 0.01) and leptin concentrations (P < 0.05) but similar lean mass (LM) compared with controls. However, leptin concentration per unit FM was identical in both groups (P = 0.3). In contrast, female patients had lower LM (P < 0.05) but similar FM to controls, yet their leptin concentration per unit FM was twice that of the controls (P < 0.05). In multiple linear regression (MLR) leptin was determined positively by FM and negatively by LM (controls r2 = 76%; patients r2 = 73%, both P < 0.0001). When controlled for gender, GH secretion in the controls was correlated negatively with leptin (r = -0.68, P < 0.01) and negatively with percentage body fat (r = -0.73, P < 0.01). In MLR, using leptin as a marker of body composition, 66% of the variability in GH secretion in the controls could be explained by gender (38%) and by leptin (28%). CONCLUSIONS: Both decreased lean mass and increased fat mass raise serum leptin concentrations in normal and growth hormone-deficient elderly subjects. Leptin is therefore a marker of body composition rather than fat mass alone. The influence of body composition on growth hormone secretion in the elderly may be mediated through leptin, acting as a peripheral signal from adipose tissue to decrease GH secretion.

Absorptiometry, Photon↗
PubMed1997

Oral administration of growth hormone (GH) releasing peptide-mimetic MK-677 stimulates the GH/insulin-like growth factor-I axis in selected GH-deficient adults.

To determine the effect of the GH releasing peptide (GHRP)-mimetic, MK-677, on the GH/insulin-like growth factor-I (IGF-I) axis in selected GH-deficient adults, we studied nine severely GH-deficient men [peak serum GH concentration in response to insulin-induced hypoglycemia of 1.2 +/- 1.5 micrograms/L, mean +/- SD (range 0.02-4.79)], age 17-34 yr, height 168 +/- 1.5 cm, body mass index 22.6 +/- 3.3 kg/m2, who had been treated for GH deficiency with GH during childhood. In a double-blind rising-dose design, subjects received once daily oral doses of 10 or 50 mg MK-677 or placebo for 4 days over two treatment periods separated by at least 28 days. Four subjects received placebo and 10 mg/day MK-677 in a cross-over fashion in periods 1 and 2. Five subjects received 10 mg and then 50 mg/day MK-677 in a sequential, rising-dose fashion in periods 1 and 2, respectively. Blood was collected every 20 min for 24 h before treatment and at the end of each period for GH measurement using an ultrasensitive assay. The drug was generally well tolerated, with no significant changes from baseline in circulating concentrations of cortisol, PRL, and thyroid hormones. Serum IGF-i and 24-H mean GH concentrations increased in all subjects after treatment with both 10 and 50 mg/day MK-677 vs. baseline. After treatment with 10 mg MK-677, IGF-I concentrations increased 52 +/- 20% (65 +/- 6 to 99 +/- 9 micrograms/L, geometric mean +/- intrasubject SE, P < or = 0.05 vs. baseline), and 24 h mean GH concentrations increased 79 +/- 19% (0.14 +/- 0.01 to 0.26 +/- 0.02 microgram/L, P < or = 0.05 vs. baseline). Following treatment with 50 mg MK-677, IGF-I concentrations increased 79 +/- 9% (84 +/- 3 to 150 +/- 6 micrograms/L, P < or = 0.05 vs. baseline) and 24-h mean GH concentrations increased 82 +/- 29% (0.21 +/- 0.02 to 0.39 +/- 0.04 microgram/L, P < or = 0.05 vs. baseline), respectively. Serum IGF binding protein-3 concentrations increased with both 10 mg (1.2 +/- 0.1 to 1.7 +/- 0.1 micrograms/L, P < or = 0.05) and 50 mg MK-677 (1.7 +/- 0.1 to 2.2 +/- 0.2 micrograms/L, P < or = 0.05). The GH response to MK-677 was greater in subjects who were the least GH/IGF-I deficient at baseline; by linear regression analysis the increase in 24-h mean GH concentration was positively related to both baseline 24-h mean GH concentration (r = 0.81, P = 0.009) and baseline IGF-I (r = 0.79, P = 0.01) for 10 mg MK-677. IGF-I responses were not significantly related to any baseline measurement. Fasting and postprandial insulin and postprandial glucose increased significantly after MK-677 treatment, and the clinical significance of these changes will need to be assessed in longer term studies. Oral administration of such GHRP-mimetic compounds may have a role in the treatment of GH deficiency of childhood onset.

Administration, Oral↗
PubMed1997

Effect of obesity and feeding on the growth hormone (GH) response to the GH secretagogue L-692,429 in young men.

GH secretion and the response to GH secretagogues are significantly diminished in obese individuals. Previous studies have shown that L-692,429 (L), a nonpeptide mimetic of GH-releasing peptide, selectively stimulates GH release in normal young men and in the elderly, who also have diminished GH secretion. A paired, two-site study examined the effects of L on GH release in 12 healthy obese (part A; mean +/- SD: age, 26.1 +/- 3.3 yr; body mass index, 35.0 +/- 3.1 kg/m2) and 10 nonobese (part B; age, 22.2 +/- 2.3 yr; body mass index, < or = 27.0) young men. In part A, placebo, low dose L (0.2 mg/kg), or high dose L (0.75 mg/kg) was administered iv over 15 min on 3 separate occasions after an overnight fast. Samples for GH, PRL, and cortisol determinations were obtained every 15 min. GH release (mean +/- SE) was significantly increased by both doses of L compared to the effect of placebo: 12.6 +/- 1.8 micrograms/L (low dose), 18.5 +/- 2.7 micrograms/L (high dose), and 0.84 +/- 0.1 microgram/L (placebo), respectively (P < 0.05). In a subset of 6 obese men, in samples collected every 5 min, the GH response to both doses of L was significantly greater than that to 1 microgram/kg GHRH. To compare the response to low dose L in the obese and to determine the effects of feeding on this response, 0.2 mg/kg L was administered as described in part A to nonobese young men after an overnight fast (fasted) or a standardized breakfast (fed; part B). Low dose L was an effective GH secretagogue in nonobese young men; however, this effect was attenuated with feeding [43.6 +/- 7.9 (fasted) vs. 17.7 +/- 4.8 (fed) micrograms/L]. Of note, the response to low dose L in fasted obese individuals was similar to that in fed nonobese individuals. The administration of L was well tolerated in both groups. We conclude that L is an effective GH secretagogue in obese and nonobese young men and may have therapeutic benefits when administered to relative (obese or elderly) or absolute GH-deficient individuals.

Adult↗
PubMed1997

Preservation of growth hormone pulsatility despite pituitary pathology, surgery, and irradiation.

Detailed assessment of physiological and pathophysiological GH secretion has, until recently, been limited by the poor sensitivity of the available assays. We have used an ultrasensitive chemiluminescence GH assay (sensitivity, 0.002 microgram/L) to study 24-h GH profiles (20-min sampling) from 24 patients who had been treated for hypothalamic-pituitary disease with surgery and irradiation and from 24 healthy control subjects matched for age, sex, and body mass index. Twenty-three of the 24 patients demonstrated pulsatile GH secretion, determined by Cluster. The median (range) area under the curve for GH, mean pulse area, mean pulse height, average valley mean level, and mean interpeak nadir were lower in the patients than in the controls [119.25 (7.273-843.600) vs. 968.539 (227.200-4625.000) min/microgram.L (P < 0.00001); 3.777 (0.288-30.850) vs. 61.390 (12.880-224.210) min/microgram.L (P < 0.00001), 0.107 (0.010-0.958) vs. 1.408 (0.368-5.050) micrograms/L (P < 0.00001), 0.074 (0.006-0.415) vs. 0.348 (0.048-2.350) microgram/L (P < 0.00001), and 0.066 (0.003-0.270) vs. 0.205 (0.021-1.838) microgram/L (P = 0.0004), respectively]. The median (range) number of pulses, mean pulse duration, and mean interval between pulses did not differ between the patients and controls [10 (4-15) vs. 10 (7-15; P = 0.36), 96.4 (68.0-220.0) vs. 104.0 (72.0-151.4) min (P = 0.65) and 128.0 (92.8-255.0) vs. 126.2 (90.0-180.0) min (P = 0.73), respectively]. The diurnal rhythm of GH secretion was present in the controls, but there was only limited evidence of residual diurnal rhythm in the patients. This study has demonstrated that GH secretion remains pulsatile in GH-deficient patients despite the mass effect of hypothalamic-pituitary pathology, pituitary surgery, and radiotherapy. With the development of potent GH secretagogues that are active orally, our findings may have important implications for the future management of GH-deficient subjects.

Age Factors↗