Main Research Findings

1) The study reports that when used in patients with recurrent gliomas, sermorelin has the potential to inhibit tumor cell proliferation through cell cycle blocking.

2) Administration of sermorelin was shown to increase levels of IGF-1 in hypogonadal males when given three times daily.

 

Selected Data

1) The study conducted by the research team of Chang et al screened several compounds for effectiveness in patients with recurrent gliomas based on transcriptomic data. The data collection was carried out in two separate phases: 325 samples were sequenced in 2016, while another 693 samples were sequenced in 2019. Because these two sets of data were generated at different times, they were treated as independent cohorts for analysis. Specifically, the 325 earlier samples constituted the discovery cohort, while the 693 later samples were designated as the validation cohort. Alongside transcriptomic data, clinical and molecular information related to each patient sample was analyzed [1].

To support the drug-related analyses, the researchers also accessed the DrugBank online database, downloading information on 4,865 different compounds. This extensive dataset provided a foundation for evaluating potential drug interactions and gene expression profiles relevant to glioblastoma. Additionally, previously validated methods described in earlier publications were used to assess mutational status of isocitrate dehydrogenase (IDH) and to determine the presence or absence of 1p/19q chromosomal co-deletions that act as two important molecular markers in glioma research. The study also incorporated external datasets from the Gene Expression Omnibus (GEO) database, specifically retrieving 38 paired patient samples across two different datasets These GEO datasets provided additional independent sources of validation for the transcriptome-based analyses.

The experimental component of the study utilized a range of chemicals and reagents, with particular focus on the peptide sermorelin. Sermorelin, a synthetic analog of growth hormone–releasing hormone (GHRH), was obtained from ACMEC Biochemical. Other standard reagents used in cell culture experiments included DMEM basal medium, fetal bovine serum, and a penicillin-streptomycin antibiotic mixture, as well as dimethyl sulfoxide (DMSO) and the Cell Counting Kit-8 (CCK-8), which was used to measure cell proliferation. These reagents provided the biochemical framework for evaluating the biological effects of sermorelin on glioblastoma cells [1].

The study employed two widely used human glioblastoma cell lines, U87 and LN229. Cells were maintained under standard conditions: cultured in DMEM supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin, and incubated at 37 °C in a humidified environment with 5% CO₂. To assess proliferation, cells were seeded in 96-well plates and treated according to the study design. The CCK-8 assay was then performed at 24 and 48 hours after treatment, following the manufacturer’s protocol. The degree of proliferation was quantified by measuring optical density at 450 nm, which reflects the metabolic activity of viable cells [1].

To analyze transcriptomic data, the researchers used Gene Set Variation Analysis (GSVA), a computational method that evaluates variation in pathway activity across samples within an expression dataset. Default parameters were applied, and gene lists for each drug were sourced from the Bader Lab geneset repository. This enabled pathway-level interpretation of the gene expression signatures associated with sermorelin treatment and related drug interactions.

To further explore the biological implications, the investigators carried out functional enrichment analyses. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted using the DAVID bioinformatics resource. These analyses were aimed at identifying the biological processes, cellular components, molecular functions, and signaling pathways influenced by sermorelin in glioblastoma models. Complementary to this, additional biological function scoring was performed using GSVA, with genesets for each biological function obtained from the AmiGO 2 web portal [1].

Immune-related analyses were also included to understand how sermorelin may influence tumor-immune interactions. For this purpose, RNA sequencing data from the CGGA database were evaluated with the CIBERSORT computational tool, which estimates the proportions of 22 immune cell subtypes infiltrating the tumor microenvironment based on gene expression data. This analysis provided insights into the immune landscape associated with glioblastoma and potential immune-modulatory effects of sermorelin [1].

Prognostic analyses were carried out to determine the clinical significance of sermorelin-related signatures. Patient survival distributions were visualized using Kaplan-Meier survival curves, and significance was tested with the log-rank test. Both univariate and multivariate Cox proportional hazards regression analyses were performed to assess the prognostic value of the drug-related signature (DRS) scores, adjusting for potential confounders. Patients with missing clinical or molecular data were excluded from these analyses to maintain statistical rigor.

Finally, statistical analysis was carried out using a combination of tests appropriate for different types of variables. Student’s t-test, one-way ANOVA, and Chi-squared tests were used to evaluate differences between groups depending on whether the data were continuous or categorical. Data visualization and additional computational analyses were performed with several R packages, including ggplot2 for graphical representation, survival for survival analyses, and corrgram for correlation visualizations [1].

In summary, the study combined large-scale transcriptomic data analysis with experimental validation to investigate the potential role of sermorelin in glioblastoma. Through rigorous use of discovery and validation cohorts, functional bioinformatics analyses, immune profiling, and prognostic modeling, the researchers established a comprehensive framework for understanding the biological and clinical relevance of sermorelin in brain tumor research.

2) Growth hormone secretagogues (GHSs), such as growth hormone–releasing peptides (GHRPs) and growth hormone–releasing hormone (GHRH) analogs, are synthetic compounds that stimulate growth hormone (GH) release in humans. When administered continuously, these agents elicit physiologic, pulsatile secretion of GH, closely mimicking natural hormone rhythms. GHRPs are short peptides, typically consisting of about six amino acids, that were initially developed as analogs of opiate drugs. However, they do not affect opiate receptor activity nor do they alter levels of other pituitary hormones. Their ability to induce GH release is distinct from the action of GHRH. Importantly, repeated administration of GHRPs desensitizes the GH response to subsequent GHRP doses, but this desensitization does not extend to GHRH. Studies have shown that the greatest enhancement in GH release occurs when GHRPs and GHRH are administered together, acting synergistically at their respective receptors. This interaction highlights a complementary mechanism that enhances natural GH release beyond what either compound achieves alone [2].

Although the clinical use of these peptides in humans remains relatively limited, existing studies suggest that GHSs can exert beneficial effects on body composition and metabolism. For instance, GHS-R agonists such as MK-0677, an orally active compound, have been demonstrated to improve body mass and exert anti-catabolic effects in several studies. These findings underscore the potential therapeutic relevance of GHSs in preserving or enhancing lean body mass.

In evaluating the effects of GH secretagogues, insulin-like growth factor 1 (IGF-1) serves as a crucial surrogate marker. Unlike GH itself, which has a very short half-life of approximately 3 to 4 minutes, IGF-1 circulates with a half-life of around 18 hours, making it a more stable and consistent measure of GH activity. IGF-1 levels closely correlate with circulating GH levels, providing insight into the downstream effects of GH stimulation. Evidence supporting the importance of pulsatile GH release comes from studies of patients with GH deficiency. In one investigation, six adults with GH deficiency received the same total daily GH dose divided into different administration schedules. More frequent dosing, either as eight smaller boluses or as continuous infusion, proved more effective in raising IGF-1 levels than two large bolus doses. These findings emphasize that not only the total dose but also the frequency and delivery method of GH or GH secretagogue therapy influences downstream IGF-1 responses and clinical outcomes [2].

Despite the variety of GHSs available, relatively few studies have examined their effects on serum hormones and body composition in men, particularly in the context of concurrent testosterone therapy. The current retrospective study was designed to address this gap by investigating the effects of a combination of GHRP-2, GHRP-6, and the GHRH agonist sermorelin in hypogonadal men receiving testosterone replacement therapy. The primary aim was to assess the impact of this combination therapy on serum hormone levels, especially IGF-1, as well as to explore whether these agents could augment the anabolic environment provided by testosterone [2].

For this study, the research team of Sigalos et al conducted a retrospective review of medical records from 105 hypogonadal men who had been prescribed the peptide combination therapy. All men were receiving testosterone therapy with the goal of increasing lean body mass and reducing fat mass. The treatment regimen consisted of 100 micrograms of each peptide, GHRP-2, GHRP-6, and sermorelin, administered subcutaneously three times daily. Compliance was assessed based on prescription refill frequency, with compliant patients defined as those refilling prescriptions within 45 days of each month’s supply. To ensure a population with suboptimal baseline GH activity, men with baseline IGF-1 levels below 200 ng/mL were included, whereas those with IGF-1 levels above this threshold were excluded.

Baseline laboratory assessments included measurements of IGF-1, total testosterone, free testosterone, estradiol, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). These measurements were obtained before the initiation of peptide therapy and repeated approximately every three to four months during treatment. Statistical analysis of the hormone data was performed using Microsoft Excel. The distribution of data was assessed by histogram analysis, and comparisons between baseline and treatment values were conducted using two-tailed Student’s t-tests. A p-value less than 0.05 was considered statistically significant, reflecting conventional thresholds for significance in biomedical research. This framework established the basis for evaluating whether combined therapy with GHRP-2, GHRP-6, and sermorelin could enhance IGF-1 and testosterone-related parameters in men already receiving testosterone therapy, and whether such a regimen could provide a physiologic and synergistic boost to the anabolic environment [2].

 

Discussion

1) The study conducted by Chang et al aimed to identify the most effective drug for patients with recurrent glioma. In total, 4,865 drugs were analyzed, and each patient sample was assigned a DRS for every drug. Patients were then stratified into primary or recurrent glioma groups, and average DRS values for each group were calculated. The difference between recurrent and primary scores was defined as an indicator of drug sensitivity: positive values signified drug resistance, while negative values reflected drug sensitivity. Out of all drugs tested, 2.34% (114 drugs) showed statistically significant differences between recurrent and primary glioma cohorts. Among them, five drugs exhibited the most significant divergence, with sermorelin emerging as the top candidate due to its lowest p-value and highest difference values in both discovery and validation cohorts [1].

Further analysis revealed that the gene encoding the growth hormone–releasing hormone receptor (GHRHR) was the primary determinant of glioma sensitivity to sermorelin. This observation was validated using patient data from two independent GEO datasets, which included paired samples of primary and recurrent gliomas. Across both datasets, GHRHR expression was found to increase in recurrent gliomas compared to their primary counterparts. This result supported the hypothesis that recurrent gliomas, which often display therapy resistance, might be more vulnerable to sermorelin. To experimentally confirm this, cell proliferation assays were conducted using U87 and LN229 glioblastoma cell lines. The CCK-8 assay demonstrated that sermorelin significantly inhibited glioma cell growth in both a dose- and time-dependent manner. Collectively, these findings positioned sermorelin as the most promising drug candidate for recurrent glioma patients, guiding the subsequent analyses in the study [1].

To better understand the clinical landscape of sermorelin responsiveness, the researchers stratified glioma patients into resistant and sensitive groups based on their DRS values. The median DRS score was used as the cutoff, with patients scoring below the median defined as sensitive. Heatmap analyses compared resistant and sensitive groups across several clinical and molecular features, including World Health Organization grade, age, gender, IDH mutation status, 1p/19q co-deletion status, and primary versus recurrent classification. With the exception of age and gender, the distribution of most characteristics was markedly asymmetrical. Patients with high-grade tumors, IDH-wildtype status, 1p/19q non-codeletion status, and recurrent disease were disproportionately represented in the sensitive group. This finding was notable because these features are generally associated with poor prognosis and therapy resistance, suggesting sermorelin may be particularly effective in otherwise refractory patients.

The correlation between sermorelin DRS and clinical features was further analyzed across both discovery and validation cohorts. In both datasets, patients with WHO grade IV gliomas had significantly lower DRS values than those with lower-grade tumors, indicating higher sensitivity to sermorelin. Similarly, patients with IDH-wildtype gliomas and 1p/19q non-codeleted tumors consistently displayed lower DRS values compared to their IDH-mutant and 1p/19q codeleted counterparts. When stratified by The Cancer Genome Atlas transcriptomic subtypes, gliomas of the mesenchymal and classical subtypes, both of which are linked to aggressive disease biology, also showed lower DRS values relative to the proneural and neural subtypes. These findings reinforced the idea that sermorelin may exert its strongest therapeutic effects in glioma subgroups associated with poor prognosis [1].

To investigate the biological mechanisms underlying sermorelin’s activity, the researchers conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Genes most strongly correlated with sermorelin were identified using Pearson correlation analysis, and the top 500 genes from both discovery and validation cohorts were subjected to functional enrichment. GO analysis revealed that sermorelin-associated genes were predominantly involved in processes linked to cell proliferation, such as nuclear division and cell cycle regulation. KEGG pathway analysis further confirmed enrichment in cell cycle pathways. These findings suggested that sermorelin inhibits glioma growth primarily by disrupting cell cycle progression and nuclear division, thereby limiting tumor cell proliferation [1].

The role of sermorelin in immune regulation was also examined. The study evaluated 7,350 biological functions confirmed by GO analysis and compared them to sermorelin’s DRS values. Sermorelin was found to be associated not only with transcription, translation, proliferation, and cell cycle regulation, but also with immune system processes. Subsequent Pearson correlation analysis showed that most immune checkpoints were negatively associated with sermorelin, suggesting a potential immune-modulatory effect. CIBERSORT analysis, which estimates tumor-infiltrating immune cell populations, revealed that CD4 naïve T cells and monocytes correlated positively with sermorelin sensitivity, while M0 macrophages correlated negatively. These results indicated that, beyond inhibiting proliferation, sermorelin may influence glioma biology by reshaping the immune microenvironment.

Given its dual roles in proliferation control and immune regulation, the prognostic implications of sermorelin were assessed. Kaplan-Meier survival analyses of 929 glioma patients demonstrated that those with lower sermorelin DRS values, indicating higher sensitivity, had significantly worse prognoses. This paradox suggested that patients with aggressive gliomas stand to benefit most from sermorelin therapy. Further subgroup analyses showed that patients who had undergone radiotherapy or concurrent chemoradiotherapy also exhibited lower DRS values and worse survival outcomes, implying that such pretreated patients may be particularly responsive to sermorelin [1]

Finally, univariate and multivariate Cox regression analyses were performed to determine whether DRS was an independent prognostic factor. Results confirmed that DRS remained significantly associated with overall survival even after adjusting for other clinical variables, including WHO grade, age at diagnosis, radiotherapy status, chemotherapy status, and 1p/19q codeletion status. This finding underscored the robustness of DRS as a prognostic marker and highlighted sermorelin’s therapeutic potential, especially for glioma patients with poor prognostic indicators.

In summary, the study identified sermorelin as the most effective FDA-approved drug for recurrent glioma through integrative bioinformatics and experimental validation. Recurrent gliomas exhibited higher GHRHR expression, and both patient-derived data and in vitro experiments supported sermorelin’s ability to inhibit glioma cell growth. The drug was particularly effective in patients with aggressive clinical and molecular profiles, such as WHO grade IV gliomas, IDH-wildtype tumors, and 1p/19q non-codeleted gliomas. Mechanistically, sermorelin appeared to act by disrupting cell cycle progression and modulating immune system processes. Importantly, patients with poorer prognoses, including those who had already received radiotherapy or CCRT, were more sensitive to sermorelin [1].

2) This study conducted by Sigalos et al evaluated the effects of growth hormone secretagogues, specifically GHRP-6, GHRP-2, and sermorelin, on IGF-1 levels and other hormonal markers in hypogonadal men receiving testosterone therapy. The cohort included fourteen men with baseline IGF-1 concentrations below 200 ng/mL. Each participant was treated with subcutaneous injections of 100 mcg of each peptide three times daily. The average age of the cohort was 33.2 years, ranging between 29 and 39 years. At baseline, mean IGF-1 was 159.5 ng/mL, total testosterone averaged 586.9 ng/dL, and free testosterone averaged 12.9 ng/dL. FSH, LH, and estradiol were all relatively low at baseline, reflecting the hypogonadal state of the participants. Treatment lasted a mean of 134 days, during which consistent increases in IGF-1 were observed at all follow-up intervals, alongside significant rises in testosterone and free testosterone after 90 days. Conversely, no significant changes were seen in FSH, LH, or estradiol across the study period, suggesting that the primary hormonal effects of the intervention were centered on IGF-1 and testosterone [2].

A noteworthy observation was that several men required concurrent use of antiestrogen therapies such as aromatase inhibitors or tamoxifen to address gynecomastia or elevated estradiol levels. Three subjects were already on antiestrogens at study initiation, while four others began during treatment, bringing the total to seven men on such therapy. When comparing outcomes, men on antiestrogen therapy had slightly lower mean IGF-1 levels than those not on antiestrogens recorded at 217.6 vs. 262.8 ng/mL, respectively. Nonetheless, both groups demonstrated significant increases in IGF-1 compared with their baseline values. The reduced IGF-1 effect observed in men on antiestrogens may be explained by the known role of estrogen in stimulating growth hormone secretion through both feedforward drive and reduction of somatostatin feedback. Estrogen also regulates IGF-1 receptor expression in some tissues, whereas antiestrogens downregulate this pathway, potentially blunting IGF-1 elevations [2].

In contrast to exogenous GH therapy, GHSs such as GHRP-2, GHRP-6, and sermorelin offer a more physiologic approach by stimulating pulsatile GH release, which in turn drives IGF-1 production within the normal physiologic range. This endogenous stimulation is thought to reduce the risk of excessive IGF-1 elevations and their associated complications. Prior safety data on the investigational GHS MK-0677, a ghrelin mimetic, demonstrated promising results across various populations, including young healthy men, obese individuals, elderly adults, and women with osteoporosis.

The current study demonstrated that the combination of GHRP-2, GHRP-6, and sermorelin successfully increased IGF-1 levels in hypogonadal men undergoing testosterone therapy, with concurrent rises in testosterone and free testosterone. These results suggest that GHSs may enhance anabolic and metabolic processes without pushing IGF-1 into supraphysiologic ranges. However, the dampened IGF-1 response seen in men on antiestrogen therapy highlights the complex interplay between estrogen signaling, GH release, and IGF-1 regulation. Prior research has shown that estrogen amplifies GH release by counteracting somatostatin inhibition and enhancing GHRH signaling, while antiestrogens may reduce IGF-1 receptor expression, thereby modifying the biological effects of IGF-1 [2].

In summary, this investigation provides early evidence that the combination of GHRP-6, GHRP-2, and sermorelin can increase IGF-1 and testosterone levels in hypogonadal men already on testosterone therapy, while maintaining other hormones largely unchanged. The study supports the concept that GHSs may provide a safer and more physiologic alternative to exogenous GH therapy by stimulating endogenous pulsatile GH release, thereby avoiding supraphysiologic IGF-1 levels [2].

 

Disclaimer

**LAB USE ONLY**
*This information is for educational purposes only and does not constitute medical advice. THE PRODUCTS DESCRIBED HEREIN ARE FOR RESEARCH USE ONLY. All clinical research must be conducted with oversight from the appropriate Institutional Review Board (IRB). All preclinical research must be conducted with oversight from the appropriate Institutional Animal Care and Use Committee (IACUC) following the guidelines of the Animal Welfare Act (AWA).

 

Citations

[1] Chang Y, Huang R, Zhai Y, et al. A potentially effective drug for patients with recurrent glioma: sermorelin. Ann Transl Med. 2021;9(5):406. doi:10.21037/atm-20-6561.

[2] Sigalos JT, Pastuszak AW, Allison A, et al. Growth Hormone Secretagogue Treatment in Hypogonadal Men Raises Serum Insulin-Like Growth Factor-1 Levels. Am J Mens Health. 2017;11(6):1752-1757. doi:10.1177/1557988317718662

What is Sermorelin

Sermorelin is a synthetic peptide that acts as a growth hormone-releasing hormone (GHRH) and prompts the release of Growth Hormone (GH) from the anterior pituitary gland. Sermorelin is clinically referred to as (GHR)1-29 NH2 indicating that the amino terminus is found at the 29th position. However, in clinical settings sermorelin is not used as a free base, but rather as an acetic acid salt. Treatment with sermorelin has been shown to increase serum concentration levels of GH and insulin-like growth factor (IGF-1).

Without supplementation of sermorelin, there are existing positive and negative feedback loops regulating the secretion of GH and somatostatin. This in turn creates a cycle similar to a circadian rhythm of GH secretion. With supplementation of sermorelin, the amplitude and frequency of GH secretion are drastically improved.

Effects of Sermorelin on Sleep Patterns and Orexin

Various animal studies have shown that there is a potential link between supplementation of sermorelin and sleep patterns. These studies have shown that sermorelin is known to increase slow-wave sleep which is when the rate of GH secretion is at its highest level. As these animals aged they showed decreased levels of slow-wave sleep as well as a 2 to 3-fold decrease in GH secretion, indicating that there is a link between GH secretion and the amount of slow-wave sleep.
Additionally, sermorelin has also been shown to affect orexins, the neurons in charge of regulating the sleep-wake cycle in animals. Due to the role of orexins in homeostasis, it has been hypothesized that orexins are regulated by the GH-axis. Dysfunctions of the orexins are related to both obesity and sleep disorders such as narcolepsy due to the overstimulation of the orexin receptors. It’s indicated that orexin plays a vital role in GH secretion, which is supported by the link between slow-wave sleep and GH secretion mentioned above. Animal studies have also shown that administration of sermorelin stimulates levels of orexins and indirectly improves levels of GH secretion (https://lotilabs.com/blog/2020/02/12/sermorelins-unique-effect-on-sleep/).

Effects of Sermorelin on Growth Delays

It has been established that sermorelin has been shown to play a role in the regulation and function of the GH-axis and secretion of GH. Sermorelin has a short half-life of only 11-12 minutes. This allows sermorelin to be administered either intravenously or subcutaneously and promotes GH secretion from the pituitary gland without affecting other hormones such as insulin, cortisol, glucose, glucagon, luteinizing hormone, or follicle-stimulating hormone.
Due to the stability of the previously listed hormones when sermorelin is administered, clinical studies were approved to begin testing on infantile mammals experiencing growth delays. The studies showed that within 6 months there was a drastic increase in the release of GH. Clinical studies will soon be moving into examining the effects that sermorelin has on muscle wasting and cognition in elderly mammals as well as lipodystrophy caused by HIV (https://onlinelibrary.wiley.com/doi/10.1002/rco2.9).

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