Treatment of Growth Hormone-Deficient Adults with Recombinant Human Growth Hormone Increases the Concentration of Growth Hormone in the Cerebrospinal Fluid and Affects Neurotransmitters

Abstract

In a double-blind, placebo-controlled trial, the effects of recombinant human growth hormone were studied on cerebrospinal fluid concentrations of growth hormone, insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), monoamine metabolites, neuropeptides and endogenous opioid peptides. Twenty patients, 10 patients in each of 2 groups, with adult-onset, growth hormone deficiency were treated for 1 month with recombinant human growth hormone (0.25 U/kg/week) or placebo. All the patients received the appropriate thyroid, adrenal and gonadal hormone replacement. In cerebrospinal fluid, the mean concentration of growth hormone increased from 13.3 ± 4.4 to 149.3 ± 22.2 µU/1 (p = 0.002), during recombinant human growth hormone treatment. The cerebrospinal fluid IGF-1 concentration increased from 0.67 ± 0.04 to 0.99 ± 0.10 µg/1 (p = 0.005) and the IGFBP-3 concentration rose from 13.4 ± 1.25 to 17.5 ± 1.83 µg/l(p = 0.002). The dopamine metabolite homovanillic acid decreased from 282.1 ± 36.0 to 234.3 ± 26.5 nmol/l (p = 0.02) and the vasoactive intestinal peptide decreased from 4.1 ± 0.6 to 3.7 ± 0.4 pmol/l (p = 0.03). Cerebrospinal fluid immunoreactive β-endorphin increased from 24.4 ± 1.8 to 29.9 ± 2.1 pmol/l (p = 0.002). There were no significant changes compared to baseline in the cerebrospinal fluid concentrations of enkephalins, dynorphin A, the norepinephrine metabolite 3-methoxy-4-hydroxyphenyl-ethyleneglycol, the serotonin metabolite 5-hydroxyindoleacetic acid, γ-aminobutyric acid, somatostatin or corticotropin-releasing factor. We conclude that treatment with recombinat human growth hormone causes a tenfold increase in growth hormone in the cerebrospinal fluid, thereby indicating that recombinant human growth hormone passes the blood-cerebrospinal fluid barrier. The cerebrospinal fluid concentrations of IGF-1 and IGFBP-3 increased significantly. Simultaneously, the cerebrospinal fluid concentrations of homovanillic acid and vasoactive intestinal peptide decreased and the concentration of β-endorphin immunoreactivities increased significantly. These changes might explain the improved quality-of-life in patients with growth hormone deficiency following replacement therapy with growth hormone.

Growth hormone therapy and Quality of Life: possibilities, pitfalls and mechanisms

“…These GH-induced modulations in neurotransmitter levels may be responsible for the positive effect of GH on mood, since similar changes are observed following successful treatment with anti-depressives (Risby et al 1987. Increased beta-endorphin levels have also been observed in the CSF of GH-treated patients in some (Johansson et al 1995) but not all studies. Beta-endorphins are produced in regions containing GH-binding activity (pituitary and hypothalamus) and are involved in exercise-induced changes in mood (Goldfarb & Jamurtas 1997).…”

“…Long-term GH replacement in GHD men decreases dopamine turnover, as indicated by reduced CSF concentrations of homovanilic acid (a dopamine metabolite) (Johansson et al 1995. The concomitant increase in CSF aspartate concentrations and N-methyl- aspartate (NMDA) receptor activation implicates excitatory amino acids in this reduced dopamine release .…”

Growth hormone induces age-dependent alteration in the expression of hippocampal growth hormone receptor and N -methyl- d -aspartate receptor subunits gene transcripts in male rats

“…injections of GH (12,13). In one of these studies a dose-dependent increase in cerebrospinal fluid GH concentrations was confirmed (13).…”

Atypical depression in growth hormone deficient adults, and the beneficial effects of growth hormone treatment on depression and quality of life

“…Other scientific approaches to this question provide supportive evidence that GH has direct effects on the CNS, affecting sleep patterns and the CSF concentrations of various neurotransmitters. The atypical nature of the depression, and the observation that GHD and its treatment does not alter CSF levels of 5HT or NE metabolites (3,4), suggests that these symptoms may not be readily amenable to conventional antidepressant medication. The results of our study suggest that patients with GH deficiency and impaired QOL and/or atypical depression should be given a trial of GH therapy, and that the effects of treatment can be gauged after only a few months.…”

“…Growth hormone treatment of GHDAs reduces the cerebrospinal fluid (CSF) concentrations of vasoactive intestinal peptide and of the dopamine metabolite, homovanillic acid (3,4), and may increase the CSF concentration of beta-endorphin (4) (although some researchers have found no effect (3)). However, GHD does not seem to alter the CSF levels of 5-hydroxytryptophan (5HT) or norepinephrine (NE) metabolites (3,4), which are usually thought to be the most significant monoamines in depression. Blunting of the GH response to provocation tests has been reported as a feature of major depression in non-GH deficient patients (5 -7).…”