Exploring the Science of Sermorelin: A Research-Based Review on Its Impacts in Health and Wellness
Sermorelin is a synthetic peptide mimicking the effects of a natural growth hormone-releasing hormone (GHRH). It is primarily used in medical settings to stimulate the production and release of growth hormone from the pituitary gland.
GHRH consists of 44 peptides, with its biological activity predominantly retained in the initial 29 peptides known as GHRH (1–29)NH2. The pituitary variant of the GHRH receptor is where most of this hormone’s neuroendocrine functions happen, but scientists are learning more about GHRH receptors in other parts of the body. The central receptor plays a vital role in regulating somatotrophs’ normal proliferation and GH synthesis and release [1]. The peripheral receptors have been implicated in roles ranging from immune system modulation to stem cell growth and proliferation in various tissues.
There are two naturally occurring analogs of GHRH, both of equal potency. They are GHRH (1–40)-OH and GHRH (1–44)-NH2. The efficacy of these peptides has been compared to sermorelin, which was found to be equal. In essence, sermorelin retains all of the regular biological activity of the natural analogs of GHRH [2].
Sermorelin consists of only the first 29 amino acids of standard GHRH. Sermorelin has been designed to mimic the actions of natural GHRH. As such, it acts on the pituitary gland and stimulates growth hormone secretion. Sermorelin can have various effects on the body by increasing the production and release of growth hormones. Research shows that Sermorelin can:
• Increase lean body mass by promoting bone and muscle growth.
• Stimulate fat burning,
• Improve nutrition in chronic illness,
• Reduce seizure activity and protect the central nervous system against disease.
• Reduce scarring following a heart attack,
• Mediate the function and health of pancreatic islet cells and
• Enhance longevity by countering some of the effects of aging.
Sermorelin is available in various formats, but the lyophilized version is best for transport and storage. Sermorelin is readily reconstituted in water and has a long shelf life, even after reconstitution. When considering where to buy sermorelin, it is essential to note that several truncated versions of GHRH are 29 amino acids in length. Sermorelin (also known as Geref) is distinguished because it contains no modified amino acids and is a direct fragment of GHRH. In other words, sermorelin is just the first 29 amino acids of GHRH without substitutions. It is important not to confuse sermorelin with tetrasubstituted GRF, modified GRF, or mod GRF.
Sermorelin: Function and Uses
Sermorelin is primarily used clinically for assessing growth hormone secretion. It is often employed in diagnostic tests to evaluate the functioning of the hypothalamic-pituitary axis, especially in cases where growth hormone deficiency is suspected [3]. Sermorelin is generally preferred over GH in these types of studies because it assesses the GH axis more comprehensively and has fewer side effects, with a lower potential for accidental overdose.
In addition to its diagnostic use, sermorelin has garnered attention for its potential therapeutic benefits in certain conditions. Some potential benefits include promoting tissue repair, increasing bone density, improving nutritional status, supporting renal function, potentially mitigating the effects of dementia, and reducing seizure activity. However, it is essential to note that further research is needed to establish the safety and efficacy of sermorelin in these specific therapeutic applications.
Growing evidence suggests that GHRH is found outside the central nervous system in various non-hypothalamic tissues and likely directly contributes to diverse cellular processes. Reproducible research demonstrates that GHRH regulates cell growth and differentiation in different cell types beyond the pituitary gland. The precise mechanisms through which GHRH influences peripheral tissues outside the pituitary gland are not yet fully understood. However, it likely involves both traditional neuroendocrine effects and local signaling pathways, such as paracrine and autocrine pathways. While progress has been made in identifying receptors for GHRH in non-pituitary tissues, there is still much to uncover about these receptors and their variants in various tumors. The incomplete understanding of non-pituitary GHRH receptors remains a significant challenge in further exploring the mechanisms of local GHRH action [4].
Sermorelin | Pulsatile Growth Hormone Release
Growth hormone-releasing hormone (GHRH) and somatostatin (SS) are thought to work together to cause pulsatile GH release in humans. This pulsatile release is a biochemical phenomenon observed in various cell and tissue types, where natural chemical products are secreted in a regular pattern over a 24-hour day. Circadian cycles typically control this pattern, which will alter to fit daylight patterns for organisms that migrate or during seasonal changes in the number of daylight hours.
Examples of hormones secreted in a pulsatile manner include insulin, thyrotropin, TRH, gonadotropin-releasing hormone, and growth hormone. Control of hormone release by the nervous system is centered in the hypothalamus. Neurons originating from the paraventricular and arcuate nuclei within the hypothalamus project to the median eminence. In this region, they release hormones into the hypophysial portal system, forming a vital connection between the hypothalamus and the pituitary gland. The hypothalamus governs endocrine function through this intricate system via the four hypothalamic-pituitary-glandular axes. New research has shown that many pituitary hormones are released in a pulsatile pattern. This suggests that the hypothalamus releases related hormones in a pulsatile pattern before the hormones are released. This pulsatile mode of secretion has been observed in hormones like luteinizing hormone (LH), follicle-stimulating hormone (FSH), and gonadotropin-releasing hormone (GnRH), shedding light on the cellular mechanisms involved in pituitary hormone pulsatility.
One reason exogenous GH therapy produces unwanted side effects is its inability to mimic the natural pulsatility of GH release from the pituitary gland. Additionally, exogenous GH is not subject to normal physiologic feedback controls, such as sleep, fasting, food consumption, exercise, and insulin release. Thus, instead of a gentle ebb and flow of GH fine-tuned by myriad other factors, exogenous GH release results in a GH peak followed by a significant trough. The trough, of course, results from suppressing the normal GH axis.
Sermorelin maintains the normal pulsatility of GH release and is also sensitive to average physiologic feedback, such as somatostatin release[5]. As a result, sermorelin avoids many of the unwanted side effects of exogenous GH administration while providing many benefits. Additionally, because it is subject to standard regulatory systems, sermorelin is safer and easier to administer than recombinant GH. An overdose of Sermorelin is nearly impossible, whereas an overdose of recombinant GH is relatively easy to produce.
Sermorelin | Exercise Response
Growth hormone increases lean body mass, reduces fat mass in adults, and enhances exercise tolerance and maximum oxygen uptake. It stands to reason that sermorelin, which increases GH levels, would enhance these effects. This is precisely what is observed.
In healthy individuals, aside from the long-term influence of GH/IGF-I status, there is an indication that the immediate GH response to exercise plays a significant role in regulating post-exercise substrate metabolism. When athletes are administered higher-than-normal doses of GH, it increases the availability of fatty acids. It reduces the loss of oxidative proteins, especially during exercise, leading to an increase in lean body mass. Some evidence suggests that a combination of GH and testosterone administration can enhance exercise performance and strength in older individuals. However, it is essential to carefully consider the potential advantages of GH in such cases in light of possible adverse effects[6]. Fortunately, peptides like sermorelin mitigate many of those adverse effects.
While most people associate muscle mass with athletic performance, it is crucial to understand that it is critical to human health. In particular, muscle mass is necessary for normal physical function and fundamental tasks like balance and locomotion. Athletes and bodybuilders seek to enhance muscle mass and strength for competitive purposes. Conversely, individuals like the elderly, astronauts, or those recovering from periods of limited activity or illness aim to increase muscle mass to improve overall functionality and enhance their quality of life. In these populations under greater physiological stress, muscle plays a crucial role as a metabolic reserve, ensuring stable glucose levels and supplying amino acids needed for various bodily functions, including those related to the internal organs, the immune system, and wound healing. Therefore, when muscle mass has diminished, an increase in muscle mass becomes essential for restoring vital life functions. Thus, muscle is more than just for athletic performance or bodybuilding; it is a critical component for an everyday, functional, healthy life.
Muscle growth in response to exercise and nutrient consumption is influenced by various factors, including the timing of intake, the type of protein or amino acids consumed, and the concurrent ingestion of other nutrients. For instance, after resistance exercise, consuming milk protein leads to a greater uptake of amino acids by the muscles compared to soy protein. The intake timing can also impact protein accumulation, with greater amino acid uptake observed when free amino acids and carbohydrates are consumed before rather than after resistance exercise. It is also obviously influenced by hormonal conditions.
Testosterone is the primary contributor to muscle growth, with research consistently showing a positive correlation between testosterone levels and overall muscle mass. This correlation stems from that testosterone increases muscle synthesis and helps recycle the byproducts of muscle breakdown. The best way to think about testosterone is as a hormone that shifts the balance of muscle buildup and breakdown towards muscle building[7].
GH does not increase muscle protein synthesis, at least not in the way that testosterone does. As a result of this finding, it was long believed that GH supplementation was not beneficial for maintaining or building muscle mass. Coupled with the peptide’s notorious side effects, research on both GH and growth hormone secretagogues was sidelined for a significant period. Fortunately, research on Sermorelin has begun to change this perspective.
There is a clear correlation between sermorelin (and similar peptides like tesamorelin) and lean body mass. Higher levels of GH are also associated with increases in lean body mass and a reduction in fat mass. Recent research indicates higher growth hormone levels are associated with increased skeletal muscle mass and grip strength. This research suggests this is likely due to GH’s effects on follistatin mRNA levels[8]. Follistatin is an antagonist of myostatin, and myostatin is a known muscle growth inhibitor. Animals lacking myostatin have significantly more muscle mass than those with normal myostatin levels. Thus, the role of sermorelin in improving muscle mass is not so much about direct anabolism as it is about preventing catabolism.
Simply put, sermorelin helps combat the breakdown of muscle. Interestingly, myostatin is thought to have evolved as a response to nutrient deficiencies. In an environment of abundance, myostatin is simply an evolutionary holdover with no natural positive effect and, arguably, some drawbacks.
Supporting this research are studies in dogs that show that chronic administration of GH leads to increased body mass due to muscle and bone mass increases. GH increases type I and type II muscle fibers, leading to overall muscle hypertrophy[9]. This increase in both fiber types is consistent with the reduced action of myostatin in muscle secondary to higher GH levels.
Finally, research supports a role for GHRH analogs in increasing insulin-like growth factor 1 (IGF-1) levels[10], [11]. IGF-1 is an anabolic peptide that inhibits apoptosis and encourages growth and cell proliferation. IGF-1 binds to the IGF-1 receptor and alters several signal cascades within cells. These signaling cascades are known to inhibit cell apoptosis and increase the production of cellular proteins, thus contributing to the muscle growth seen following the administration of sermorelin and other growth hormone secretagogues.
Sermorelin | Immune Function
Growth hormone receptors are found on various cells in the immune system. Research shows that sermorelin begins to affect the immune system within four weeks of administration. These effects include:
• Increases in cells expressing the CD71 marker of proliferation,
• A significant rise in the CD54+ marker of immune activation,
• An increase in the number of monocytes, and
• An increase in the percentage of B lymphocytes in the blood.
One study, for instance, reveals that administering a GHRH analog to elderly participants activates their immune systems. This immune response was observed in both males and females after four weeks and was marked by an increase in the proliferation of immune cells. Moreover, the relative counts of B cells and monocytes increased, while there were no changes in T or NK cell populations. Both T and B cell functionality also showed improvement, characterized by heightened responsiveness to mitogens and increased circulating immunoglobulins. There was also a notable increase in lymphocytes expressing the IL-2 receptor. This immune enhancement resulting from GHRH analog treatment occurred without apparent adverse effects, and no antibodies against the GHRH analog were detected[12].
Data from more than one study suggest that administering GHRH analog activates all elements of the peripheral immune system. T cells may play a central role in coordinating the immune response to GHRH. Given that immune cells express GHRH, GH, IGF-I, and their corresponding receptors, GHRH may initiate its mitogenic effect by first stimulating the expression of the IL-2 receptor gene. This could lead to the proliferation and activation of T cells at naturally occurring concentrations of IL-2. The result is an increase in regulatory T cells that control the immune system to a large degree.
Research also indicates that sermorelin is a potent regulator of macrophage activity. In mouse models, administration of sermorelin and other GHRH agonists leads to decreased inflammation by reducing the infiltration of macrophages and leukocytes, as well as the production of TNF-α, IL-1β, and monocyte chemotactic protein-1 (MCP-1) in tissue. This effect on macrophages is beneficial in cancer [14][15].
Sermorelin | Heart Health
Research has been ongoing into the potential effects of the sermorelin peptide and other GHRH agonists on heart health. General findings indicate that GHRH is highly beneficial for heart health, particularly in heart failure following cardiac injury. There has been extensive research on using Sermorelin to prevent cardiac remodeling after a heart attack. The benefits of Sermorelin and other GHRH agonists for heart health include:
• Cardiovascular Benefits: Some studies suggest that Sermorelin may offer potential cardiovascular benefits. For example, when released appropriately, GH can positively affect cardiac function, increasing cardiac output and enhancing heart contractility.
• Improved Cardiac Function: Research indicates that Sermorelin might enhance cardiac function in certain conditions. Animal studies, for instance, have linked sermorelin to increased cardiac output and improved left ventricular function.
• Endothelial Function: Growth hormone, when administered in appropriate doses, has shown positive effects on endothelial function, crucial for maintaining healthy blood vessels. Enhanced endothelial function can contribute to better heart health.
Research suggests that sermorelin may counteract dysfunctional cardiomyocyte relaxation by modifying the phosphorylation of cardiac muscle fibers. This suggests that sermorelin may directly enhance heart function by improving the efficiency of the heart muscle itself. This function would be beneficial both in the context of disease and for enhancing performance in a healthy state[13].
The cardiac benefits of Sermorelin are not limited to preventing adverse outcomes. Studies in rats indicate that sermorelin has modulatory effects even after damage. For instance, sermorelin can reverse ventricular remodeling after a heart attack, thus improving the functional recovery of the heart. Rats in models of heart failure treated with the peptide exhibit superior hemodynamic profiles compared to untreated rats. The treated rats experienced reduced damage to cardiac muscle along with increased mitosis of both heart muscle cells and supportive cells[14]. In other words, these rats undergo cardiac regrowth, which is generally not observed with sermorelin, as less than 2% of the stem cells in the heart produce viable cardiomyocytes under normal conditions.
These results have also been replicated in pigs, which is significant because pig hearts share structural and functional similarities with human hearts. Pig hearts resemble human hearts, so pig valves are often used in human valve replacement procedures. A 2016 study involving pigs demonstrated that Sermorelin:
• Reduces cell death in cardiomyocytes,
• Increases the production of extracellular matrix components necessary for adequate healing,
• Promotes the growth of blood vessels in damaged tissue and
• Decreases the production of substances that contribute to damaging inflammation[15].
Given the seriousness of heart disease and the substantial funding available for research in this field, it is unsurprising that investigating sermorelin’s role in heart protection is a primary focus of peptide research. Sermorelin has shown promise in improving diastolic function, reducing scar size, and enhancing capillary growth in the context of heart disease. With well-established animal models for heart disease and a pressing need for effective treatments, research in this area will likely continue to expand.
