Tesamorelin: Mechanism of Action

1. Receptor Target — GHRH Receptor

Tesamorelin acts as a specific agonist for the GHRH receptor (GHRHr), a seven-transmembrane G protein-coupled receptor (GPCR) located on somatotroph cells in the anterior pituitary gland. Binding potency is comparable to endogenous GHRH. [7]

2. DPP-4 Resistance

The trans-3-hexenoic acid modification at the N-terminal Tyr1 acts as a chemical shield against DPP-4 cleavage. Native GHRH is rapidly degraded (T½ ~5 min); Tesamorelin's modification extends stability to ~26–38 min. [3]

3. Downstream Signaling Cascade

Gₛ → Adenylyl Cyclase → cAMP → PKA → Ca²⁺ Influx → GH Exocytosis:

1. Receptor activation triggers the Gₛα subunit
2. Gₛα stimulates adenylyl cyclase, converting ATP to cAMP
3. Elevated cAMP activates Protein Kinase A (PKA)
4. PKA opens voltage-gated Ca²⁺ channels → calcium influx
5. Ca²⁺ triggers exocytosis of pre-stored GH vesicles
6. Simultaneously, cAMP promotes GH gene transcription (new GH synthesis) [7]

The product supplied here is for research use only regardless of regulatory status of related formulations.

4. Selectivity

Tesamorelin is highly selective for the GHRH receptor. It does not significantly alter TSH, LH, ACTH, or Prolactin levels. Unlike GHRPs (e.g., Ipamorelin), it does not bind the ghrelin receptor. [9]

5. Cellular and Tissue-Level Effects

Adipose Tissue:

• Selectively reduces visceral adipose tissue (VAT) by ~15–18%, minimal effect on subcutaneous fat [10]
• Activates hormone-sensitive lipase (HSL), inhibits lipoprotein lipase (LPL)
• Visceral fat cells have higher GH receptor density, explaining selectivity

Hepatic (Liver):

• Reduces hepatic fat (~37% relative reduction) [11]
• Reduces de novo lipogenesis, enhances fatty acid oxidation
• Prevents progression of liver fibrosis (10.5% vs 37.5% progression, P=0.04) [11]

Musculoskeletal:

• Promotes protein synthesis, increases trunk lean mass and muscle area [12]
• Improves muscle density (myosteatosis reduction)

Nervous System:

• Improves executive function and verbal memory in MCI/aging [13]
• Increases GABA levels, modulates amyloid-beta pathways

6. Comparison with Related Molecules

7. Pharmacokinetics

Parameter	Value
Route	Subcutaneous (abdomen)
Bioavailability	<4% (SC)
Half-Life (T½)	~26–38 min (SC, 2 mg); ~11 min (1.28 mg WR)
Standard Dose	2 mg SC daily (SV); 1.28 mg SC daily (WR)
GH Pulsatility	Preserved (natural pulses, IGF-1 feedback intact)
Metabolism	Proteolytic cleavage; no formal human metabolism studies
Animal T½	21–45 min (dogs)