Predictors of improvement in endothelial function after exercise training in a diverse sample of postmenopausal women.

BACKGROUND: Endothelial dysfunction measured via flow-mediated dilation (FMD) is associated with greater risk of future hypertension and cardiovascular events in postmenopausal women. Aerobic exercise training has been shown to improve endothelial function in Caucasian populations, but has not been evaluated specifically in African Americans. This has clinical importance due to the increased prevalence of cardiovascular disease in African Americans. METHODS: In the present pilot study, 8 African American (age: 55.8±1.7 years, peak oxygen uptake [VO2 peak]: 21.0±3.9 mL/kg/minute, body mass index [BMI]: 30.1± 6.3 kg/m(2)) and 16 Caucasian (age: 57.2±5.9 years, VO2 peak: 21.8±3.7 mL/kg/minute, BMI: 29.3±5.2 kg/m(2)) sedentary postmenopausal women underwent brachial artery FMD measurements before and after 12 weeks of aerobic exercise training. FMD was quantified by comparing B-mode ultrasound images of the brachial artery at rest and following reactive hyperemia after 5 minutes of forearm occlusion. Participants performed aerobic exercise training 4 days per week for 12 weeks. RESULTS: Despite improvements in fitness in both groups, aerobic exercise training did not significantly improve FMD in African American (5.8% to 5.7%, p=0.950) or Caucasian postmenopausal women (5.7% to 6.6%, p=0.267). In women with the greatest impairment in endothelial function at baseline (FMD<4.5%), a significant improvement in FMD was observed, independent of race, following exercise training (2.2% to 6.2%, p=0.007). CONCLUSION: The benefits of aerobic exercise training on endothelial function in postmenopausal women are most pronounced in women with endothelial dysfunction prior to training and do not appear to be affected by race.

Physical deconditioning as a cause of breathlessness among obese adolescents with a diagnosis of asthma.

BACKGROUND: Obese children frequently complain of breathlessness. Asthma and obesity can both contribute to the symptoms during exercise, and this symptom can contribute to a diagnosis of asthma in these children. Despite the high prevalence of obesity few studies have investigated the cardiopulmonary physiology of breathlessness in obese children with a diagnosis of asthma. METHODS: In this case-control study, thirty adolescents between age 12 and 19 were studied with baseline spirometry and a cardiopulmonary exercise test. Ten adolescents were normal controls, ten had obesity without a diagnosis of asthma, and ten had obesity with a history of physician-diagnosed asthma. RESULTS: Baseline characteristics including complete blood count and spirometry were comparable between obese adolescents with and without a diagnosis of asthma. During exercise, obese asthmatic and obese non-asthmatic adolescents had significantly reduced physical fitness compared to healthy controls as evidenced by decreased peak oxygen uptake after adjusting for actual body weight (21.7 ± 4.5 vs. 21.4 ± 5.4 vs. 35.3 ± 5.8 ml/kg/min, respectively). However, pulmonary capacity at the peak of exercise was comparable among all three groups as evidenced by similar pulmonary reserve. CONCLUSION: In this study, breathlessness was primarily due to cardiopulmonary deconditioning in the majority of obese adolescents with or without a diagnosis of asthma.

Evaluation of racial differences in resting and postprandial endothelial function in postmenopausal women matched for age, fitness and body composition.

OBJECTIVE: We investigated endothelial function at rest and after a high-fat meal challenge in African American (AA) and Caucasian postmenopausal women matched for age, body mass index, percent fat and fitness level. DESIGN: Pilot study. SETTING: University of Virginia General Clinical Research Center. PARTICIPANTS: Eight AA and 8 Caucasian postmenopausal women. INTERVENTION: PARTICIPANTS underwent a VO2 peak treadmill protocol, percent fat assessment, and brachial artery flow-mediated dilation measurements (baseline and 4 hours following a high-fat meal). MAIN OUTCOMES MEASURES: Baseline and postprandial flow mediated dilation (FMD) following a high-fat meal. RESULTS: FMD values were similar in AA (5.4%, 95% CI: 3.3, 7.4) and Caucasian women (4.0%, 95% CI: 2.0, 6.1). There was no significant change in FMD from baseline to four hours following the meal challenge within groups (AA: .9%, P = .397, Caucasian: 2.3%, P = .063) or between groups (P = .449), despite a significant increase in triglycerides (AA: 81.8 mg/dL, P < .001, Caucasian: 99.7 mg/dL, P = .004). CONCLUSIONS: The present pilot study found that when postmenopausal AA and Caucasian women are matched for age, fitness and body composition, reported racial differences in resting endothelial function were not observed. Additionally, there were no racial differences in postprandial endothelial function or metabolism following a high-fat meal.

Administration of recombinant human GHRH-1,44-amide for 3 months reduces abdominal visceral fat mass and increases physical performance measures in postmenopausal women.

OBJECTIVE: A recent study indicated that twice-daily s.c. administration of a high dose of recombinant human GHRH-1,44-amide (GHRH) for 90 days can alter body composition in healthy older men. No data establish whether this is also true in postmenopausal women. The present study tests the hypothesis that the same GHRH regimen applied in women will: (i) elevate both IGF-I and GH concentrations; and (ii) reduce abdominal visceral fat mass, augment total body water and enhance functional performance. DESIGN: Ten postmenopausal volunteers underwent baseline study and then received 1 mg GHRH twice daily s.c. for 3 months. METHODS: Statistical comparisons were made with pre-intervention baseline data. RESULTS: GHRH administration stimulated: (i) a mean 98 +/- 14% elevation of overnight GH concentrations after administration of the peptide for 1 and 3 months (P < 0.005); (ii) a sustained 71 +/- 3.5% rise in IGF-I concentrations over the interval from 2 weeks to 3 months (P < 0.0012); (iii) a 16 +/- 7% reduction in abdominal visceral fat mass (P = 0.029) and a 14 +/- 5% increase in tri-tiated water space (P < 0.025); (iv) an abbreviation of the times required to walk 30 m (P = 0.015) and ascend two flights of stairs (P = 0.003). Most (70%) subjects experienced local skin reactivity. There were no systemic adverse events. CONCLUSIONS: A 3-month regimen of GHRH supplementation in postmenopausal women can stimulate GH and IGF-I production, reduce abdominal visceral fat and improve selected measures of physical performance, while inducing significant local skin reactivity.

Gender modulates sequential suppression and recovery of pulsatile growth hormone secretion by physiological feedback signals in young adults.

The basic mechanisms that drive the renewal of GH pulses in the human are not understood. Recent ensemble models predict that pulse regeneration requires quenching of an ongoing GH pulse by somatostatin outflow and evocation of a new burst by rebound GHRH release. We reasoned that related principles might explain why women consistently maintain higher-amplitude GH secretory bursts than men. Accordingly, the present study tests the hypothesis that gender modulates the successive dynamics of GH feedback and escape in the morning fasting, when GH pulses are larger in women. To this end, we infused single iv pulses of recombinant human (rh) GH (0, 1, and 3 microg/kg) in eight young men and six women on separate randomly ordered mornings fasting and quantitated serial inhibition and recovery of GH secretion by frequent sampling, immunochemiluminometry, a deconvolution procedure, and regularity analysis. Statistical contrasts revealed gender-comparable peak concentrations and kinetics of rhGH. However, women differed from men by way of: (1) 3.5- and 4.0-fold less feedback suppression of GH secretory-burst mass; (2) more irregular patterns of GH release during negative feedback; and (3) 12-and 14-fold greater postnadir rebound-like GH secretion after rhGH pulses. Mechanistic analyses based on a minimal feedback construct predicted that women generate higher endogenous secretagogue stimulation per unit somatostatin outflow than men. In summary, negative feedback induced by near-physiological GH pulses unmasks prominent gender-related contrasts in hypothalamo-pituitary autoregulation in young adults. A frugal but sufficient explanation of the ensemble outcomes is that women sustain greater hypothalamo-pituitary agonist input than men.

Contributions of gender and systemic estradiol and testosterone concentrations to maximal secretagogue drive of burst-like growth hormone secretion in healthy middle-aged and older adults.

To test whether concentrations of estradiol and testosterone predict GH responses to mechanistically distinct secretagogues in healthy older adults, we studied 16 volunteers (n = 10 men, n = 6 women, age 49-72 yr) in each of six randomly ordered sessions as follows: 1) saline; 2) l-arginine; 3) aerobic exercise; 4) GHRH; 5) GH-releasing peptide (GHRP)-2; and 6) somatostatin-induced rebound. Statistical comparisons disclosed that stimulus type (P < 0.001) and the interaction between gender and stimulus type (P = 0.023) determine GH secretion. In women, each secretagogue, except exercise and somatostatin-induced rebound, stimulated GH secretion by 2.6- to 6.4-fold over saline/rest (P < 0.023). In men, somatostatin-induced rebound drove GH secretion by 4.6-fold (P = 0.004), exercise by 16-fold (P < 0.001), and other secretagogues by 18- to 109-fold over saline/rest (each P < 0.001). Gender comparisons disclosed greater GH secretion in men than women after somatostatin-induced rebound (P = 0.008) and GHRP-2 injection (P < 0.001) and conversely greater GH secretion in women than men after saline (P = 0.013). Regression analysis showed that individual concentrations of estradiol (r = 0.80, P = 0.002) and testosterone (r = 0.63, P = 0.008) and their combination (r = 0.86, P < 0.001) strongly predict responses to GHRP-2 only. We conclude that among healthy middle-aged and older adults, the action of GHRP is uniquely determined by gender and physiological concentrations of testosterone and estradiol.

Sustained growth hormone (GH) and insulin-like growth factor I responses to prolonged high-dose twice-daily GH-releasing hormone stimulation in middle-aged and older men.

Postulated mechanisms underlying the relative hyposomato-tropism of aging include reduced hypothalamic drive by GHRH. To test this notion, we administered 1 mg (n = 11) vs. 4 mg (n = 11) recombinant human GHRH-1,44-amide s.c. twice daily for 3 months in a double-blind, parallel-cohort design to 22 healthy men (ages, 53-68 yr). After 3 months, GHRH elevated: overnight GH concentrations from 0.71 +/- 0.19 to 1.74 +/- 0.39 microg/liter (P < 0.001; 1 mg) and from 0.80 +/- 0.15 to 5.12 +/- 0.40 microg/liter (P < 0.001; 4 mg) and IGF-I concentrations from 117 +/- 14 to 234 +/- 20 microg/liter (P = 0.007; 1 mg) and from 147 +/- 13 to 286 +/- 22 microg/liter (P < 0.001; 4 mg). Only the higher GHRH dose also increased total body water (tritium space; P = 0.024) and fat-free mass (dual-energy x-ray absorptiometry; P = 0.021), and reduced total abdominal adiposity (computed axial tomography scan; P = 0.042). Both supplementation schedules shortened the time required to walk 30 m and ascend four flights of stairs (P < 0.025 each). Lower extremity strength, aerobic capacity, and bone mineral density did not change. Local injection site reactions were common. We conclude that sc administration of a large dose of GHRH (4 mg) twice daily for 3 months elevates GH and IGF-I concentrations, increases total body water and fat-free mass, reduces total abdominal adiposity, and enhances certain performance measures in healthy aging men but causes local skin reactions.

Age and secretagogue type jointly determine dynamic growth hormone responses to exogenous insulin-like growth factor-negative feedback in healthy men.

The primary cause of waning GH and IGF-I concentrations in healthy aging adults is not established. To test the postulate that age influences negative feedback by IGF-I in a secretagogue-specific fashion, 17 normal men (nine young and eight older) each completed eight randomly ordered injections of placebo or recombinant human (rh) IGF-I (20 microg/kg sc), followed by saline/rest, aerobic exercise, GHRH (1 microg/kg iv bolus), or GH-releasing peptide-2 (1 microg/kg iv bolus) stimulation. GH secretion was monitored by sampling blood every 10 min for 7 h, high-sensitivity immunochemiluminometric assay, and deconvolution analysis conditioned on prior pulse-onset times and biexponential kinetics. Analysis of covariance showed that age (P = 0.028), secretagogue (P < 0.001), and rhIGF-I (P < 0.005) individually determine pulsatile GH secretion and exhibit a strong 3-fold interaction (P < 10(-5)). Post hoc comparisons revealed that elderly subjects manifest less IGF-I inhibition of a maximal GHRH stimulus (P = 0.013 vs. young), blunted initial IGF-I suppression of fasting GH release (P = 0.038), and impaired IGF-I feedback on the regularity of GH secretion (P = 0.023). Age stratum did not influence peak IGF-I and nadir GH concentrations or rhIGF-I-induced inhibition of GH secretion stimulated by exercise or GH-releasing peptide-2. In summary, experimental elevation of IGF-I concentrations unmasks reduced rhIGF-I-dependent feedback inhibition of fasting and GHRH-stimulated GH secretion in healthy older men, indicating that aging selectively modulates the autoinhibition process.