Key Points:

Ibutamoren increases serum IGF-1 levels through changes in IGF-binding proteins, particularly IGFBP-3.

Ibutamoren’s mechanism of action involves stimulating the GH-IGF-1 axis, leading to increased secretion of GH and IGF-1, IGF-binding proteins (IGFBP-1 to IGFBP-6). No significant changes in cortisol, prolactin, thyroid hormone, or insulin levels: suggesting a specific effect on the GH-IGF-I axis without altering other endocrine functions.

The exact effects of Ibutamoren on individual IGFBPs may differ, but its overall impact is to modulate the IGF system, regulating bioavailability and function of IGF-1.

IGFBP increases the half-life of IGF in circulation and blocks its potential binding to the insulin receptor.

IGFBP-3 is the most abundant circulating IGFBP, and binds IGF1 and IGF2 with equal affinity.

IGFBP-3 has a number of IGF-independent actions, including modulation of angiogenesis, the physiological process through which new blood vessels form from pre-existing vessels. A mechanism that contributes to IGFBP-3-induced inhibition of prostate cancer.

IGFBP-3 also has a role in DNA damage repair, activating autophagy in bronchial epithelial cells. IGFBP-3 interacts with receptors including RXR-α, PPAR-γ, the vitamin D receptor and Nur77, leading to some of its effects on apoptosis, preventing faulty cells from replicating, eliminating sick cells, and forming new cells.

Dose-dependent response: The study below demonstrated a dose-dependent effect of MK-677 on GH and IGF-I levels, with higher doses (0.8 mg/kg/day) resulting in greater increases.Further research is needed to fully understand the specific interactions between Ibutamoren and IGF binding proteins:

Clinical Trials

A clinical trial involving growth hormone-deficient children found that Ibutamoren treatment resulted in a median increase of 0.4 μg/L (range, -0.9 to 1.5) in serum IGFBP-3 levels (P = 0.01).

A clinical trial involving young men found that Ibutamoren increased plasma IGF-I levels in a dose-dependent manner. IGFBP-3 levels were increased only with the highest dosage. MK-677 had no effect on cortisol profiles.

A clinical trial in healthy elderly subjects, Ibutamoren produced significant increases in fasting glucose (5.4 +/- 0.3 to 6.8 +/- 0.4 mmol/L at 4 weeks; P < 0.01 vs. baseline) and IGF-binding protein-3. Circulating cortisol concentrations did not change.

IGFBPs have well-defined cellular actions:

IGFBP-1 Metabolism and diabetes, fetal growth
IGFBP-2 Tumourigenesis, obesity
IGFBP-3 Sphingosine kinase interactions, autophagy, nuclear actions
IGFBP-4 Bone biology, prenatal IGF targeting
IGFBP-5 Fibrosis, angiogenesis
IGFBP-6 Immune regulation, neuropathologies

References:
https://pubmed.ncbi.nlm.nih.gov/11452249/
https://pubmed.ncbi.nlm.nih.gov/8768828/
https://pubmed.ncbi.nlm.nih.gov/8954023/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5900387/
https://academic.oup.com/jcem/article/83/2/320/2865101?login=false
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232603/
https://jme.bioscientifica.com/view/journals/jme/61/1/JME-17-0254.xml