Tesamorelin

It has been postulated that IGF-1 is the main anabolic mediator of growth hormone, potentially working to stimulate growth and inhibit programmed cell death.(1) On the other hand, it is suggested that growth hormone itself is lipolytic, inducing the breakdown of fats in specific adipose depots, such as abdominal and visceral fat depots. Tesamorelin appears to stimulate the release of growth hormone and, consequently, IGF-1, potentially interacting with GHRH receptors in the cells of the anterior pituitary gland.

When Tesamorelin interacts with the GHRH receptor, it is hypothesized that this interaction could alter the receptor's structure, potentially initiating communication pathways within the cell. It is also theorized that Tesamorelin could improve the production of cyclic adenosine monophosphate (cAMP) in certain cells. This process may occur through the stimulation of adenylate cyclase, an enzyme that converts adenosine triphosphate (ATP) into cAMP. Increased cAMP levels can lead to the activation of protein kinase A (PKA), an enzyme considered critical for transmitting signals within cells. Activated PKA can phosphorylate various target proteins, triggering a cascade of cellular responses.

The conjectural stimulation of the GHRH receptor by Tesamorelin and the cAMP-PKA signaling pathway could promote the secretion and distribution of growth hormone (hGH) from somatotroph cells in the pituitary gland. Research indicates that this peptide can lead to an estimated 69% increase in overall growth hormone levels, measured by area under the curve (AUC), and a reported 55% increase in the mean growth hormone pulse area. However, it does not appear to influence the frequency or maximum levels of growth hormone pulses. Additionally, IGF-1 levels apparently increased by 122%.(3)

The N-terminal and C-terminal ends of the GHRH molecule are altered in Tesamorelin, potentially granting stability to the peptide and possibly increasing the compound's resistance to enzymatic deactivation compared to natural GHRH.(4) Focusing on specific alterations, the C-terminal end of Tesamorelin is modified by the addition of a trans-3-hexenoic acid group. It is believed that this particular change, often referred to as omega amino acid modification, potentially reinforces the peptide's defense against enzymatic degradation. At the other end, the N-terminal is modified by the attachment of an acetyl group, represented by the chemical notation CH₃CO-. This acetylation could improve not only the molecule's stability but also its biological activity. As a result of these specific modifications, Tesamorelin is chemically designated as N-(trans-3-hexenoyl)-[Tyr1]hGRF(1–44)NH2 acetate, highlighting the specific alterations made to the peptide.

Chemical Composition

• Molecular Formula: C221H366N72O67S
• Molecular Weight: 5136 g/mol
• Other Known Titles: (3E)-hex-3-enoylsomatoliberin

Lipodystrophy models refer to abnormal or pathological fat distribution and metabolism. The main characteristic of lipodystrophy is irregular fat distribution in depots, leading to fat loss (lipoatrophy) from specific areas and accumulation of excess fat (lipohypertrophy) in other regions. This abnormal fat distribution is often associated with severe negative metabolic changes, including insulin resistance, elevated cholesterol and triglyceride levels. Test models exhibiting lipodystrophy report low GH and IGF-1 levels. Researchers studying the action and potential impact of Tesamorelin suggest that the peptide may positively influence lipid metabolism, especially in lipodystrophy models.

For example, two phase III studies(6) were conducted with 806 test subjects over 26 weeks, followed by another 26-week extension. Each of the 806 test subjects had immunodeficiencies and lipodystrophy. Subjects were divided into two groups; one group with 543 subjects was presented with Tesamorelin, and the remaining 263 subjects were presented with a placebo for 26 weeks. After this duration, Tesamorelin subjects were again randomly divided into 2 groups, in which one group continued with Tesamorelin influence and the other half was presented with a placebo for another 26 weeks. At week 26, researchers observed a significant decrease in visceral adipose tissue level among Tesamorelin subjects, at least 15.4%. Additionally, triglyceride and cholesterol levels were reported significantly decreased compared to the placebo group.

Researchers postulate that severe immunodeficiencies can induce non-alcoholic fatty liver disease (NAFLD), which in clinical cases is reported in nearly 40% of HIV-positive test models.(7) In this study,(5) 61 HIV test subjects with high liver fat fraction (HFF) were selected as test models. These subjects were influenced with Tesamorelin or a placebo for 12 months. The HFF rate was monitored at the end of the study. After 12 months, researchers reported that 35% of subjects presented with Tesamorelin exhibited an apparent reduction in HFF rate of less than 5% versus only 4% of placebo-receiving subjects exhibited any HFF reduction. There was no reported alteration in glucose levels.

In this clinical study,(8) immunodeficient models with mild cognitive impairment were observed. The primary intention of this study was to determine the potential effect of Tesamorelin on neurological functioning. 100 subjects, over 40 years old, participated in this trial and underwent daily Tesamorelin presentation for 6 months, followed by entire absence of Tesamorelin influence for the next 6 months. Tesamorelin was then reintroduced once daily for another 6 months. The primary outcome of this study was reported in changes in neurocognitive performance measured by the Global Deficit Score (GDS) after 6 and 12 months. This study is ongoing and final results have not been published.

The main objective of this study(9) was to determine any potential Tesamorelin might exhibit in altering insulin sensitivity. In this clinical trial setting, 53 type II diabetes test subjects were observed in this randomized 12-week trial. Subjects were divided into three groups, each receiving a lower or higher concentration of Tesamorelin or a placebo. After the 12-week study period, fasting glucose concentration, glycosylated hemoglobin, and diabetes control were measured. There was no significant reduction reported in any of these parameters. Results from all three groups appeared to be indifferent.

In one investigation, potential impacts of Tesamorelin on the structural quality of muscle tissues were evaluated using computed tomography (CT) scans.(10) Computed tomography (CT) is an imaging tool that combines X-rays and computer technology to produce detailed images of internal structures. Findings from this study tentatively suggested a potential association between Tesamorelin and improvements in overall muscle tissue density and volume. Specific muscle groups, particularly the rectus abdominis, psoas major, and paraspinal muscles, were observed to exhibit more notable variations. These variations consisted of increased muscle density and volume or decreased fat within muscle tissue. From a statistical perspective, alterations in muscle density and size or reduction in fat content in these specific muscles were significantly different compared to results from a control group receiving a placebo.

Visceral obesity involves the accumulation of excess fat around and within internal organs, a condition often observed in lipodystrophy models, a disorder characterized by abnormal fat cell distribution. This form of excessive fat accumulation is potentially linked to several metabolic problems. These problems include insulin resistance, a diminished capacity to respond to insulin leading to elevated blood glucose levels. Additionally, visceral obesity is associated with the development of atherosclerosis, a condition where plaque builds up in arteries, elevated low-density lipoprotein (LDL) cholesterol levels, and hyperuricemia, an excess of uric acid. The importance of these models extends beyond aesthetic concerns, indicating that lipodystrophy can precipitate profound metabolic disturbances. By addressing these challenges, Tesamorelin, a synthetic form of growth hormone-releasing factor, has been proposed as a possibly positive pathway for further development. Research on Tesamorelin has suggested it can lead to a reduction of up to 25% in visceral fat among lipodystrophy models.(11)