Mark L. Hartman

Enhanced basal and disorderly growth hormone secretion distinguish acromegalic from normal pulsatile growth hormone release.

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 < 10(-12); fasted, P < 10(-7)) 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.

Growth hormone release during acute and chronic aerobic and resistance exercise: recent findings.

AbstractExercise is a potent physiological stimulus for growth hormone (GH) secretion, and both aerobic and resistance exercise result in significant, acute increases in GH secretion. Contrary to previous suggestions that exercise-induced GH release requires that a ’threshold’ intensity be attained, recent research from our laboratory has shown that regardless of age or gender, there is a linear relationship between the magnitude of the acute increase in GH release and exercise intensity. The magnitude of GH release is greater in young women than in young men and is reduced by 4-7-fold in older individuals compared with younger individuals. Following the increase in GH secretion associated with a bout of aerobic exercise, GH release transiently decreases. As a result, 24-hour integrated GH concentrations are not usually elevated by a single bout of exercise. However, repeated bouts of aerobic exercise within a 24-hour period result in increased 24-hour integrated GH concentrations.Because the GH response to acute resistance exercise is dependent on the work-rest interval and the load and frequency of the resistance exercise used, the ability to equate intensity across different resistance exercise protocols is desirable. This has proved to be a difficult task. Problems with maintaining patent intravenous catheters have resulted in a lack of studies investigating alterations in acute and 24-hour GH pulsatile secretion in response to resistance exercise. However, research using varied resistance protocols and sampling techniques has reported acute increases in GH release similar to those observed with aerobic exercise.In young women, chronic aerobic training at an intensity greater than the lactate threshold resulted in a 2-fold increase in 24-hour GH release. The time line of adaptation and the mechanism(s) by which this training effect occurs are still elusive. Unfortunately, there are few studies investigating the effects of chronic resistance training on 24-hour GH release.The decrease in GH secretion observed in individuals who are older or have obesity is associated with many deleterious health effects, although a cause and effect relationship has not been established. While exercise interventions may not restore GH secretion to levels observed in young, healthy individuals, exercise is a robust stimulus of GH secretion. The combination of exercise and administration of oral GH secret agogues may result in greater GH secretion than exercise alone in individuals who are older or have obesity. Whether such interventions would result in favourable clinical outcomes remains to be established.

Normal Control of Growth Hormone Secretion

Growth hormone (GH) is secreted by the anterior pituitary gland in a pulsatile fashion under the regulation of two hypothalamic peptides: GH-releasing hormone (GHRH) stimulates GH synthesis and secretion while somatostatin inhibits GH release. Studies in rats, sheep and humans indicate that whereas GHRH is required for the initiation of GH pulses, the amplitude of GH pulses is modulated by somatostatin. In humans, these interactions result in a pattern of volleys of GH-secretory pulses with intervening periods of relative secretory quiescence. The amplitude and frequency of GH-secretory pulses are regulated by a complex array of external and internal stimuli including age, gender, menstrual cycle phase, pubertal status, nutrition, sleep, body composition and exercise. Changes in plasma concentrations of gonadal hormones, insulin and insulin-like growth factor-I likely mediate the effects of several of these factors. A greater understanding of the physiology of GH secretion will enable the development of future strategies to enhance GH secretion in GH-deficient states including the use of GH secretagogues and modification of nutrition and exercise habits.

Intensity of acute exercise does not affect serum leptin concentrations in young men

Purpose: We examined the effects of exercise intensity on serum leptin levels. Methods: Seven men (age = 27.0 yr; height = 178.3 cm; weight = 82.2 kg) were tested on a control (C) day and on 5 exercise days (EX). Subjects exercised (30 min) at the following intensities: 25% and 75% of the difference between the lactate threshold (LT) and rest (0.25 LT, 0.75 LT), at LT, and at 25% and 75% of the difference between LT and peakOV2? (1.25 LT, 1.75 LT). Results: Kcal expended during the exercise bouts ranged from 150 ± 11 kcal (0.25 LT) to 529 ± 45 kcal (1.75 LT), whereas exercise + 3.5 h recovery kcal ranged from 310 ± 14 kcal (0.25 LT) to 722 ± 51 kcal (1.75 LT). Leptin area under the curve (AUC) (Q 10-min samples) for all six conditions (C + 5 Ex) was calculated for baseline (0700–0900 h) and for exercise + recovery (0900–1300 h). Leptin AUC for baseline ranged from 243 ± 33 to 291 ± 56 ng~mL-1 X min; for exercise + recovery results ranged from 424 ± 56 to 542 ± 99 ng~mL-1 X min. No differences were observed among conditions within either the baseline or exercise + recovery time frames. Regression analysis confirmed positive relationships between serum leptin concentrations and percentage body fat (r = 0.94) and fat mass (r = 0.93, P < 0.01). Conclusion: We conclude that 30 min of acute exercise, at varying intensity of exercise and caloric expenditure, does not affect serum leptin concentrations during exercise or for the first 3.5 hours of recovery in healthy young men.

Growth Hormone and Nutrition

The regulation of growth hormone (GH) secretion in humans is a complex process which comprises more than stimulation by GH-releasing hormone and suppression by somatostatin. Although these two hypothalamic hormones are the primary regulators of GH secretion, they most likely function as the final pathway through which numerous factors influence GH synthesis and secretion. Some of the modulators of GH secretion include neurotransmitters, circulating glucose, insulin-like growth factor I and gonadal steroid concentrations. Age, nutrition and body composition are also related to the amount and pattern of GH secretion in humans. The influence of nutritional status on GH secretion is becoming more clearly defined.

Exercise training decreases the growth hormone (GH) response to acute constant-load exercise

To assess the influence of exercise training on the growth hormone (GH) response to acute exercise, six untrained males completed a 20-min, high-intensity, constant-load exercise test prior to and after 3 and 6 wk of training (the absolute power output (PO) during each test remained constant x PO = 182.5 +/- 29.5 W). Training increased (pre- vs post-training) oxygen uptake (VO2) at lactate threshold (1.57 +/- 0.33 L.min-1 vs 1.97 +/- 0.24 L.min-1 P < or = 0.05). VO2 at 2.5 mM blood lactate concentration ([HLa]) (1.83 +/- 0.38 L.min-1 vs 2.33 +/- 0.38 L.min-1, P < or = 0.05), and VO2peak (3.15 +/- 0.54 L.min-1 vs 3.41 +/- 0.47 L.min-1, P < or = 0.05). Power output at the lactate threshold (PO-LT) increased with training from 103 +/- 28 to 132 +/- 23W (P < or = 0.05). Integrated GH concentration (20 min exercise + 45 min recovery) (microgram.L-1 x min) after 3 wk (138 +/- 106) and 6 wk (130 +/- 145) were significantly lower (P < or = 0.05) than pre-training (238 +/- 145). Plasma epinephrine and norepinephrine responses to training were similar to the GH response (EPI-pre-training = 2447 +/- 1110; week 3 = 1046 +/- 144; week 6 = 955 +/- 322 pmol.L-1; P < or = 0.05; NE pre-training = 23.0 +/- 5.2; week 3 = 13.4 +/- 4.8; week 6 = 12.1 +/- 6.8 nmol.L-1; P < or = 0.05). These data indicate that the GH and catecholamine response to a constant-load exercise stimulus are reduced within the first 3 wk of exercise training and support the hypothesis that a critical threshold of exercise intensity must be reached to stimulate GH release.

Randomized Clinical Trial Comparing Basal Insulin Peglispro and Insulin Glargine in Patients With Type 2 Diabetes Previously Treated With Basal Insulin: IMAGINE 5

OBJECTIVE To evaluate the efficacy and safety of basal insulin peglispro (BIL) versus insulin glargine in patients with type 2 diabetes (hemoglobin A1c [HbA1c] ≤9% [75 mmol/mol]) treated with basal insulin alone or with three or fewer oral antihyperglycemic medications. RESEARCH DESIGN AND METHODS This 52-week, open-label, treat-to-target study randomized patients (mean HbA1c 7.42% [57.6 mmol/mol]) to BIL (n = 307) or glargine (n = 159). The primary end point was change from baseline HbA1c to 26 weeks (0.4% [4.4 mmol/mol] noninferiority margin). RESULTS At 26 weeks, reduction in HbA1c was superior with BIL versus glargine (−0.82% [−8.9 mmol/mol] vs. −0.29% [−3.2 mmol/mol]; least squares mean difference −0.52%, 95% CI −0.67 to −0.38 [−5.7 mmol/mol, 95% CI −7.3 to −4.2; P < 0.001); greater reduction in HbA1c with BIL was maintained at 52 weeks. More BIL patients achieved HbA1c <7% (53 mmol/mol) at weeks 26 and 52 (P < 0.001). With BIL versus glargine, nocturnal hypoglycemia rate was 60% lower, more patients achieved HbA1c <7% (53 mmol/mol) without nocturnal hypoglycemia at 26 and 52 weeks (P < 0.001), and total hypoglycemia rates were lower at 52 weeks (P = 0.03). At weeks 26 and 52, glucose variability was lower (P < 0.01), basal insulin dose was higher (P < 0.001), and triglycerides and aminotransferases were higher with BIL versus glargine (P < 0.05). Liver fat content (LFC), assessed in a subset of patients (n = 162), increased from baseline with BIL versus glargine (P < 0.001), with stable levels between 26 and 52 weeks. CONCLUSIONS BIL provided superior glycemic control versus glargine, with reduced nocturnal and total hypoglycemia, lower glucose variability, and increased triglycerides, aminotransferases, and LFC.

Prospective Safety Surveillance of GH-Deficient Adults: Comparison of GH-Treated vs Untreated Patients.

Context: In clinical practice, the safety profile of GH replacement therapy for GH-deficient adults compared with no replacement therapy is unknown. Objective: The objective of this study was to compare adverse events (AEs) in GH-deficient adults who were GH-treated with those in GH-deficient adults who did not receive GH replacement. Design and Setting: This was a prospective observational study in the setting of US clinical practices. Patients and Outcome Measures: AEs were compared between GH-treated (n = 1988) and untreated (n = 442) GH-deficient adults after adjusting for baseline group differences and controlling the false discovery rate. The standardized mortality ratio was calculated using US mortality rates. Results: After a mean follow-up of 2.3 years, there was no significant difference in rates of death, cancer, intracranial tumor growth or recurrence, diabetes, or cardiovascular events in GH-treated compared with untreated patients. The standardized mortality ratio was not increased in either group. Unexpected AEs (GH-treated vs untreated, P ≤ .05) included insomnia (6.4% vs 2.7%), dyspnea (4.2% vs 2.0%), anxiety (3.4% vs 0.9%), sleep apnea (3.3% vs 0.9%), and decreased libido (2.1% vs 0.2%). Some of these AEs were related to baseline risk factors (including obesity and cardiopulmonary disease), higher GH dose, or concomitant GH side effects. Conclusions: In GH-deficient adults, there was no evidence for a GH treatment effect on death, cancer, intracranial tumor recurrence, diabetes, or cardiovascular events, although the follow-up period was of insufficient duration to be conclusive for these long-term events. The identification of unexpected GH-related AEs reinforces the fact that patient selection and GH dose titration are important to ensure safety of adult GH replacement.

Physiological role of somatostatin on growth hormone regulation in humans

Growth hormone (GH) secretion in man is pulsatile and this pattern is regulated by both GH-releasing hormone (GHRH) and somatostatin. A large body of experimental evidence in both man and animals supports the model that bursts of GH secretion are mediated by a reduction of tonic hypothalamic somatostatin secretion. Our studies have been performed in normal subjects with frequent blood sampling for GH measurements (from 20-minute to 30-second intervals); the data have been analyzed by computer algorithms to objectively determine pulse characteristics and, in some studies, to estimate both pituitary secretion and clearance rates using deconvolution analysis. The studies include profiles of GH secretion in normal men and women in fed and fasted states; analysis of GH secretion during sleep; and administration of GHRH during different stages of sleep and after sleep deprivation. The variable GH response to exogenous GHRH and the attenuated response after 6 hours of GHRH infusion to GHRH, while not to hypoglycemia, as well as the pulsatile profile of GH secretion in response to continuous GHRH infusions (24 hours to 14 days), all support the thesis that it is hypothalamic somatostatin that determines the timing of bursts of GH secretion. This is further confirmed by the profile of GH secretion in a patient with ectopic GHRH secretion. Recently, we have initiated studies with the novel synthetic GH releasing hexapeptide, HisDTrpAlaTrpDPheLysNH2 (GHRP). Our studies show that it acts synergistically with GHRH. Several lines of evidence suggest that GHRP stimulates GH secretion independently of GHRH receptors and acts at both the hypothalamic and pituitary levels. It may act to functionally antagonize somatostatin.

Neuroendocrine regulation of growth hormone secretion.

Growth hormone (GH) secretion is controlled by many factors, including stage of development, age, gonadal steroids, body composition, nutritional state, time of day and whether the subject is asleep or awake. Understanding regulation of GH secretion is important since this hormone regulates not only growth, but also the partitioning of nutrients and body composition. There is increasing evidence that there is a basic ultradian rhythm of GH secretion. The NSF Center studies will be facilitated by 3 major efforts: (a) improvement of sensitivity of GH assays to permit accurate description of GH pulses; (b) use of biomathematical models to objectively determine GH pulse characteristics, as well as calculation of secretion rates to facilitate the study of the relationship between neural controls and GH secretion; and (c) use of the tau mutant hamster and the new mouse mutant animal models. By manipulation of the endogenous circadian clock in these animal models it will be possible to study the relationship between endogenous circadian systems and ultradian GH rhythms.