Growth Hormone and IGF-1
Growth hormone (GH) and its primary mediator, insulin-like growth factor 1 (IGF-1), coordinate critical aspects of metabolism, body composition, and cellular function that directly relate to ME/CFS symptoms. The growth hormone axis regulates protein synthesis and muscle mass maintenance, lipolysis (fat breakdown) and glucose metabolism, bone density and connective tissue integrity, immune function and wound healing, and cognitive function and mood. GH/IGF-1 deficiency could therefore contribute to the muscle weakness, metabolic dysfunction, and cognitive impairment characteristic of ME/CFS.
1 Evidence for GH/IGF-1 Axis Dysfunction
Research on the GH/IGF-1 axis in ME/CFS has produced conflicting findings, likely reflecting the heterogeneity of patient populations and the complexity of growth hormone regulation. Some studies document clear abnormalities, while others find normal GH dynamics, suggesting that GH dysfunction characterizes a subset of ME/CFS patients rather than representing a universal feature.
Bennett et al. (1997) (Bennett et al. 1997) documented significantly lower serum IGF-1 levels in ME/CFS patients compared to healthy controls, accompanied by reduced nocturnal secretion of growth hormone. IGF-1 serves as the primary mediator of GHβs anabolic effects, produced predominantly in the liver in response to GH stimulation and acting on peripheral tissues to promote protein synthesis, muscle growth, and metabolic regulation. Low IGF-1 despite normal or near-normal GH secretion suggests either hepatic resistance to GH or impaired liver function affecting IGF-1 synthesis. However, contradicting these findings, other rigorous studies found no differences in basal IGF-1 or IGF-binding protein (IGFBP) levels between ME/CFS patients and controls, normal urinary growth hormone excretion, and similar GH responses to provocative testing. These inconsistencies highlight the challenge of identifying reliable biomarkers in a heterogeneous disease and suggest the need for subgroup stratification based on clinical phenotypes or other biomarkers.
2 Growth Hormone Treatment Trial
Moorkens et al. (2000) conducted a randomized, double-blind, placebo-controlled trial of growth hormone treatment in ME/CFS patients with documented low IGF-1 levels (Moorkens, Wynants, and Abs 2000). The study involved 20 patients receiving 12 weeks of active treatment followed by a 9-month open-label phase. Results demonstrated clear physiological effects: mean serum IGF-1 increased from 173 \(\pm\) 46 \(\mu\)g/L to 296 \(\pm\) 89 \(\mu\)g/L (p\(<\) 0.001), fat-free mass significantly increased, and total body water increased, confirming the anabolic effects of GH. However, clinical outcomes were mixed: quality of life measures did not show significant improvement overall, though notably, 4 patients resumed work after prolonged illness, suggesting substantial benefit in a subset.
The dissociation between clear physiological effects (increased IGF-1, improved body composition) and limited symptom improvement suggests that while GH deficiency may contribute to certain ME/CFS features (particularly muscle weakness and poor exercise tolerance), it is not the primary driver of fatigue, post-exertional malaise, or cognitive symptoms. This pattern aligns with the multi-system nature of ME/CFS pathophysiology, where correcting a single hormonal deficit proves insufficient to restore overall function.
3 Mechanisms and Clinical Implications
Several mechanisms could explain GH/IGF-1 axis dysfunction in ME/CFS, each with distinct therapeutic implications:
Falsifiability: weakly β Falsified if GH stimulation tests show normal pituitary responsiveness and hepatic IGF-1 production is normal despite the proposed suppressive mechanisms
Multiple non-exclusive mechanisms may contribute to growth hormone axis dysfunction. Hypothalamic dysfunction may reduce GH-releasing hormone (GHRH) secretion, paralleling the HPA axis hypofunction discussed earlier. The NIH study documented temporal-parietal junction and broader brain abnormalities that could affect hypothalamic regulation (Walitt et al. 2024). Hepatic resistance to GH action may impair IGF-1 synthesis despite adequate GH secretion, potentially reflecting the mitochondrial dysfunction and oxidative stress documented in Chapter Energy Metabolism and Mitochondrial Function. Cytokine-mediated suppression may inhibit the GH axis, as chronic inflammation suppresses both GH secretion and IGF-1 synthesis while inducing IGF-1 resistance at target tissues. Finally, sleep disruption may reduce nocturnal GH pulses; the majority of daily GH secretion occurs during deep sleep, particularly slow-wave sleep, which is disrupted in ME/CFS.
The clinical implications of these findings remain uncertain. GH treatment showed physiological effects but limited symptom benefit in the controlled trial, suggesting it may help selected patients but is not a universal solution. The expense, need for daily injections, and potential adverse effects (fluid retention, carpal tunnel syndrome, glucose intolerance) argue for restricting GH treatment to patients with documented IGF-1 deficiency and careful monitoring of both physiological parameters and functional outcomes. Alternative approaches targeting upstream causes (sleep improvement, inflammation reduction, mitochondrial support) might prove more effective than hormone replacement alone.