Recombinant human growth hormone and recombinant human insulin-like growth factor I diminish the catabolic effects of hypogonadism in man: metabolic and molecular effects.

Severe gonadal androgen deficiency can have profound catabolic effects in man. Hypogonadal men develop a loss of lean body mass, increased adiposity, and decreased muscle strength despite normal GH and insulin-like growth factor I (IGF-I) concentrations. We designed these studies to investigate whether GH or IGF-I administration to male subjects with profound hypogonadism can diminish or abolish the catabolic effects of testosterone deficiency. Moreover, we also examined the nature of the interactions among GH, IGF-I, and androgens in specific genes of the im system. A group of 13 healthy subjects (mean age, 22 +/- 1 yr) was studied at baseline (D1) and 10 weeks after being made hypogonadal using a GnRH analog (GnRHa; D2). At 6 weeks from baseline they were started on either recombinant human (rh) IGF-I (60 microg/kg, sc, twice daily) or rhGH (12.5 microg/kg, sc, daily) for 4 weeks. On each study day subjects had infusions of L-[(13)C]leucine; indirect calorimetry; isokinetic dynamometry of the knee extensors; determination of body composition (dual energy x-ray absortiometry) and hormone and growth factor concentrations, as well as percutaneous muscle biopsies. Their data were compared with those of previously studied male subjects who received only GNRHA: Administration of rhIGF-I and rhGH to the hypogonadal men had similar effects on whole body metabolism, with maintenance of protein synthesis rates, fat oxidation rates, and fat-free mass compared with the eugonadal state, preventing the decline observed with hypogonadism alone. This was further amplified by the molecular assessment of important genes in muscle function. During rhIGF-I treatment, im expression of IGF-I declined, and IGF-binding protein-4 increased, similar to the changes during GnRHa alone. However, rhGH administration was associated with a marked increase in IGF-I and androgen receptor messenger ribonucleic acid concentrations in skeletal muscle with a reciprocal decline in IGF-binding protein-4 expression in the hypogonadal men. The gene expression for myostatin did not change. These effects were accompanied by a much greater increase in plasma IGF-I concentrations after rhIGF-I (225 +/- 32 vs. 768 +/- 117 microg/L) compared with the concentrations achieved during rhGH (217 +/- 20 vs. 450 +/- 19 microg/L). We conclude that 1) rhGH and rhIGF-I both may be beneficial in preserving lean body mass and sustaining rates of protein synthesis during states of severe androgen deficiency in man; 2) GH may affect the im IGF system via an a paracrine, local production of IGF-I; 3) androgens may be necessary for the full anabolic effect of GH/IGF-I in man. These hormones, particularly GH, may play a role in the treatment of hypogonadal men rendered hypogonadal pharmacologically or those unable to take full testosterone replacement. The latter requires further study.

Insulin-like growth factor I and growth hormone (GH) treatment in GH-deficient humans: differential effects on protein, glucose, lipid, and calcium metabolism.

We examined the effects of recombinant human (rh) insulin-like growth factor I (IGF-I) vs. rhGH in a variety of metabolic paths in a group of eight severely GH-deficient young adults using an array of contemporary tools. Protein, glucose, and calcium metabolism were studied using stable labeled tracer infusions of L-[1-13C]leucine, [6,6-2H2]glucose, and 42Ca and 44Ca; substrate oxidation rates were assessed using indirect calorimetry; muscle strength was determined by isokinetic and isometric dynamometry of the anterior quadriceps, as well as growth factors, hormones, glucose, and lipid concentrations in plasma before and after 8 weeks of rhIGF-I (60 microg/kg, sc, twice daily), followed by 4 weeks of washout, then 8 weeks ofrhGH (12.5 microg/kg-day, sc); the treatment order was randomized. In the doses administered, rhIGF-I and rhGH both increased fat-free mass and decreased the percent fat mass, with a more robust decrease in the percent fat mass after rhGH; both were associated with an increase in whole body protein synthesis rates and a decrease in protein oxidation. Neither hormone affected isokinetic or isometric measures of skeletal muscle strength. However, rhGH was more potent than rhIGF-I at increasing lipid oxidation rates and improving plasma lipid profiles. Both hormones increased hepatic glucose output, but rhGH treatment was also associated with decreased carbohydrate oxidation and increased glucose and insulin concentrations, indicating subtle insulin resistance. Neither hormone significantly affected bone calcium fluxes, supporting the concept that these hormones, by themselves, are not pivotal in bone calcium metabolism. In conclusion, rhIGF-I and rhGH share common effects on protein, muscle, and calcium metabolism, yet have divergent effects on lipid and carbohydrate metabolism in the GH-deficient state. These differences may allow for better selection of treatment modalities depending on the choice of desired effects in hypopituitarism.

Testosterone deficiency in young men: marked alterations in whole body protein kinetics, strength, and adiposity.

To investigate specific effects of androgens on whole body metabolism, we studied six healthy lean men (mean +/- SEM age, 23.2 +/- 0.5 yr) before and after gonadal steroid suppression with a GnRH analog (Lupron), given twice, 3 weeks apart. Primed infusions of [13C]leucine, indirect calorimetry, isokinetic dynamometry, growth factor measurements, and percutaneous muscle biopsies were performed at baseline (D1) and after 10 weeks of treatment (D2); each subject served as his own control. Testosterone concentrations were markedly suppressed after 10 weeks of treatment (D1, 535 +/- 141 ng/dL; D2, 31 +/- 9). Leucine's rate of appearance (index of proteolysis) was markedly suppressed after 10 weeks of hypogonadism (-13%; P = 0.01) as well as the nonoxidative leucine disposal, an index of whole body protein synthesis (-13%; P = 0.01) without any changes in plasma amino acid concentrations. All subjects studied after 10 weeks showed a decrease in fat-free mass, as measured by skinfold calipers and dual emission x-ray absortiometry scans (D1, 56.5 +/- 2.9 kg; D2, 54.4 +/- 2.5; P = 0.005), and an increase in percent fat mass (D1, 19.2 +/- 2.5%; D2, 22.2 +/- 2.5; P = 0.001). Rates of lipid oxidation decreased (-31%; P = 0.05) after treatment, with parallel changes in resting energy expenditure (-9%; P = 0.05). Mean and peak GH concentrations (measured every 10 min for 6 h) and GH production rates did not decrease after testosterone deficiency, with an actual increase in basal secretion (P < 0.02). Plasma insulin-like growth factor I (IGF-I) concentrations did not change significantly after 10 weeks of treatment (D1, 227 +/- 44 micrograms/L; D2, 291 +/- 60; P = 0.08). Isokinetic dynamometry of leg extensors at 60 degrees and 180 degrees/s was also decreased after 10 weeks of hypogonadism. Total ribonucleic acid (RNA) was isolated from muscle biopsy samples, and ribonuclease protection assays were performed using human complementary DNA clones for IGF-I, IGF-binding protein-4, myosin, and actin. Ten weeks after Lupron treatment, messenger RNA (mRNA) concentrations of IGF-I decreased significantly, whereas there was a trend toward higher IGF-binding protein-4 concentrations, with no change in myosin or actin mRNA concentrations. In conclusion, testosterone deficiency in young men is associated with a marked decrease in measures of whole body protein anabolism, decreased strength, decreased fat oxidation, and increased adiposity. These effects of testosterone deficiency are independent of changes in peripheral GH production and IGF-I concentrations, even though im IGF-I mRNA concentrations decrease. These data suggest a direct effect of androgens on whole body lipid and protein metabolism.

The stretch-shortening cycle of the quadriceps femoris muscle group measured by isokinetic dynamometry.

The ability to measure the stretch-shortening cycle of isolated muscle groups has been limited. The purpose of this study was to measure the stretch-shortening cycle of the quadriceps femoris muscle group. Twenty-four volunteer subjects, 12 men and 12 women, participated in one test session; five men and five women also participated in a retest session; to examine the reliability of the test. A concentric contraction of the left quadriceps was measured for peak torque and time to peak torque on a Biodex isokinetic dynamometer under three conditions: 1) passive stretch before a concentric contraction, 2) isometric preload before a concentric contraction, and 3) eccentric preload before a concentric contraction. Conditions 2 and 3 showed a significant increase in peak torque production compared to condition 1 (p < 0.01). A significant difference was found for all three conditions between the men and women, with the men producing greatest peak torques. Conditions 2 and 3 also showed a significantly decreased time to peak torque compared with condition 1 (p < 0.01). The testing protocol was found to have high reliability. This testing protocol could be used to further study the stretch-shortening cycle in the quadriceps femoris muscle group.