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2.6 - 7th December 1997



Metabolism 1997 Jan;46(1):89-96

Effects of single nightly injections of growth hormone-releasing hormone (GHRH 1-29) in healthy elderly men.

Vittone J, Blackman MR, Busby-Whitehead J, Tsiao C, Stewart KJ, Tobin J, Stevens T, Bellantoni MF, Rogers MA, Baumann G, Roth J, Harman SM, Spencer RG

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Age-related reductions in growth hormone (GH) and insulin-like growth factor-I (IGF-I) may contribute to decreased muscle mass and strength in older persons. The relationship of this phenomenon to skeletal muscle bioenergetics has not been reported. We sought to determine whether administration of GH-releasing hormone (GHRH) would sustain increases in GH and IGF-I and improve skeletal muscle function and selected measures of body composition and metabolism. We measured GH secretion, muscle strength, muscle histology, and muscle energy metabolism by phosphorus nuclear magnetic resonance spectroscopy (31P-NMRS), body composition, and endocrine-metabolic functions before and after 6 weeks of treatment. Eleven healthy, ambulatory, non-obese men aged 64 to 76 years with low baseline IGF-I levels were treated at home as outpatients by nightly subcutaneous self-injections of 2 mg GHRH for 6 weeks. We measured GH levels in blood samples obtained every 20 minutes from 8:00 PM to 8:00 AM; AM serum levels of IGF-I, IGF binding protein-3 (IGFBP-3), and GH binding protein (GHBP); muscle strength; muscle histology; the normalized phosphocreatine abundance, PCr/[PCr + Pi], and intracellular pH in forearm muscle by NMRS during both sustained and ramped exercise; body composition by dual-energy x-ray absorptiometry (DEXA); lipid levels; and glucose, insulin, and GH levels during an oral glucose tolerance test (OGTT). GHRH treatment increased mean nocturnal GH release (P < .02), the area under the GH peak ([AUPGH] P < .006), and GH peak amplitude (P < .05), with no change in GH pulse frequency or in levels of IGF-I, IGFBP-3, or GHBP Two of six measures of muscle strength, upright row (P < .02) and shoulder press (P < .04), and a test of muscle endurance, abdominal crunch (P < .03), improved. GHRH treatment did not alter exercise-mediated changes in PCr/[PCr + Pi] or intracellular pH, but decreased or abolished significant relationships between changes in PCr/[PCr + Pi] or pH and indices of muscle strength. GHRH treatment did not change weight, body mass index, waist to hip ratio, DEXA measures of muscle and fat, muscle histology, glucose, insulin, or GH responses to OGTT, or lipids. No significant adverse effects were observed. These data suggest that single nightly doses of GHRH are less effective than multiple daily doses of GHRH in eliciting GH- and/or IGF-I-mediated effects. GHRH treatment may increase muscle strength, and it alters baseline relationships between muscle strength and muscle bioenergetics in a manner consistent with a reduced need for anaerobic metabolism during exercise. Thus, an optimized regimen of GHRH administration might attenuate some of the effects of aging on skeletal muscle function in older persons.

Atherosclerosis 1997 May;131(1):73-78

Aging of the vascular wall: serum concentration of elastin peptides and elastase inhibitors in relation to cardiovascular risk factors. The EVA study.

Bizbiz L, Alperovitch A, Robert L

Laboratoire de Biologie Cellulaire, Universite Paris VII, France.

The relations of biological markers of extracellular matrix (plasma elastin peptides and elastase inhibitors) to the clinical history of cardiovascular diseases and risk factors for atherosclerosis were examined in a large population study (the EVA Study) on vascular and cognitive aging performed in 1389 men and women aged 59-71 years. A moderate decrease in elastin peptides was observed in women with a self-reported history of coronary heart disease (P < 0.091) and stroke (P < 0.03) as well as with diabetes (P < 0.043). Similar but non-significant trends were found in men. Furthermore, elastin peptides were significantly and positively correlated to HDL-cholesterol and apolipoprotein A1 in both sexes. On the other hand, elastase inhibitor titers were significantly higher in women than in men. A moderate increase was also found in men (P < 0.097) and women (P < 0.068) with a history of coronary heart disease that reached significance level after pooling both sexes (P < 0.014). Furthermore, elastase inhibitor titers were significantly and positively related to fibrinogen and C reactive protein in either sex. No consistent associations were observed between both biological markers of extracellular matrix and age, blood pressure, body mass index and tobacco or alcohol consumption. These results suggest that a decrease in elastin peptides and an increase in elastase inhibitors might be associated with risk factors of atherogenesis as well as with atherosclerosis-related diseases.

Recent Prog Horm Res 1997;52:215-244

Growth hormone-releasing hormone and growth hormone-releasing peptide as therapeutic agents to enhance growth hormone secretion in disease and aging.

Thorner MO, Chapman IM, Gaylinn BD, Pezzoli SS, Hartman ML

Department of Medicine, University of Virginia, Charlottesville 22908, USA.

Growth hormone (GH) secretion is pulsatile and is tightly regulated. In this chapter the effects of aging, nutrition, the feedback effects of IGF-I, and the role of body composition in the decline of GH secretion will be discussed. In GH-deficient adults there is an increase in the amount of intra-abdominal (visceral) fat. Similarly, with increasing age, there is an increase in visceral fat and there is a tight correlation between 24-hour GH release and visceral fat in the elderly. This may have serious metabolic consequences, including insulin resistance and increased cardiovascular risk. There are at least four potential mechanisms for the age-related decline in GH secretion: 1) decreased release of growth hormone releasing-hormone (GHRH); 2) increased release of somatostatin; 3) enhanced sensitivity to IGF-I feedback; and 4) decreased somatotroph mass. The latter two potential mechanisms are discussed. There is little evidence that there is any change in sensitivity to IGF-I feedback with aging and the somatotroph cell mass appears to be preserved in older subjects. The GH axis may be stimulated by either GHRH or by growth hormone-releasing peptide (GHRP) and related compounds. Chronic therapy with GHRH in GH-deficient children restores GH secretion and accelerates linear growth. Mutations of the GHRH receptor lead to GH deficiency and short stature. This indicates the essential role of GHRH in regulation of GH secretion. Growth hormone releasing peptide was discovered in 1981. Recently, the GHRP/GH secretagogue receptor has been cloned and orally active GHRP mimetics have been developed. One such compound, MK-677, stimulates pulsatile GH secretion and its effects persist for 24 hours. Oral administration of MK-677 for a month in the elderly demonstrates that this route stimulates a physiologic pattern of GH secretion. The amplitude of the GH pulses was increased but the number of GH pulses was unchanged. Thus, in older individuals, the amount of GH secreted in 24 hours is restored toward that seen in young adults. This compound also enhances GH secretion in GH-deficient adults who had been GH-deficient during childhood. The development of stable, orally active molecules to stimulate the GHRP/GH secretagogue receptor is a practical reality. These GH secretagogues may have a therapeutic role in short stature and adult GH deficiency. In addition, the use of GH secretagogues in normal aging merits investigation, as growth hormone may regulate body composition in older adults.

J Clin Endocrinol Metab 1997 Jan;82(1):129-135

A low starting dose of genotropin in growth hormone-deficient adults.

Janssen YJ, Frolich M, Roelfsema F

Department of Endocrinology, Leiden University Hospital, The Netherlands.

We investigated the effect of 12 weeks of recombinant human GH therapy given in three different doses on serum insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) in patients with GH deficiency (GHD). We used low doses of recombinant human GH (Genotropin), as we and others recently found a strong decrease in physiological GH production with age in healthy controls, especially in those older than 30 yr. Sixty patients with GHD (aged 20-70 yr) were randomized to one of the three dose groups. Group 1 used a dose of 0.6 IU/day for 12 weeks. Group 2 started at a dose of 0.6 IU for 4 weeks followed by 1.2 IU/day for 8 weeks. Group 3 used 0.6 IU for 4 weeks, followed by 1.2 IU/day for 4 weeks and 1.8 IU/day thereafter. IGF-I concentrations (nanomoles per L) were determined by RIA after extraction and purification on ODS-silica columns. The measurement of IGFBP-3 (milligrams per L) was performed by RIA. The three groups were equal with regard to age, sex and body mass index. At the start of the study, we found lower levels of both serum IGF-I and IGFBP-3 in childhood-onset GHD than in adult-onset GHD. Moreover, there was a gender difference; female GHD patients had lower serum IGF-I levels than male patients. Serum IGF-I levels were low in both childhood-onset and adult-onset GHD. Serum IGFBP-3 levels, however, were low in patients with childhood-onset GHD, but normal in patients with adult-onset GHD. After 12 weeks of treatment, IGF-I levels were low normal in the low dose group and normal in groups 2 and 3 of both adult-onset and childhood-onset GHD. In adult-onset GHD, serum IGFBP-3 increased to high normal levels in all groups, whereas it increased to low normal levels in childhood-onset GHD. This study demonstrates differences in the biochemical characteristics of childhood-onset and adult-onset GHD. In patients with adult-onset GHD, serum IGFBP-3 levels are not significantly decreased and, therefore, cannot be used as a screening method for GHD or as a dose-finding parameter. GH therapy at doses of 0.6 and 1.2 IU/day in male and female patients, respectively, is, in general, able to increase serum IGF-I into the normal range after 12 weeks of treatment, without reaching supranormal levels of serum IGF-I. This dose could, therefore, be a starting dose in GH-deficient adults.



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