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6.03.1.9 Sermorelin
Sermorelin is an analog of growth hormone-releasing hormone (GHRH) primarily used for diagnostic purposes. It is a 29-amino acid-containing fragment of endogenous human GHRH, also represented as GHRH (1–29). Sermorelin is the shortest fully functional synthetic fragment of GHRH.15 It was marketed under the trade name of Geref by Serono Laboratories, but the FDA recently listed it as a “discontinued drug product.”
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Chapter
Therapeutics
Sermorelin is licensed as a diagnostic test for secretion of growth hormone. It is also used for the treatment of growth hormone deficiency in children. However, products containing sermorelin were withdrawn from the United States market by the manufacturer in November 2002.
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Use for diagnosis and treatment
Sermorelin, a functional peptide fragment of GHRH(1–29), has been used in the diagnosis and treatment of children with idiopathic growth hormone deficiency.13 Tesamorelin, a stabilized synthetic peptide analog of GHRH(1–44), received US Food and Drug Administration approval in 2010 for the treatment of lipodystrophy in HIV patients under highly active antiretroviral therapy, and was investigated for effects on certain cognitive functions in adults with cognitive impairment as well as healthy older adults.14
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Human Pharmacokinetics
Sermorelin is very rapidly cleared from the plasma due to degradation. Amino acid substitutions reduce clearance and prolong the disappearance half time Soule et al. (1994).
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Which Analogue to Use?
The potency of the two naturally occurring analogues of GHRH, GHRH(1–40)-OH and GHRH(1–44)-NH2 and the truncated GHRH(1-29)-NH2 (sermorelin)335 has been compared and found to be equal. Of these three compounds, only sermorelin has been approved for clinical use. However, it has been withdrawn by the manufacturer and is not commercially available in the United States. Another GHRH analogue, tesamorelin, described under therapeutic uses of GHRH, has not been evaluated for diagnostic use as a GH secretagogue.
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Basic Chemistry
Chemical structure Structure Chemical formula C149H246N44O42S Properties Physical properties Molecular weight 3357.91 Solubility
Human Pharmacokinetics
Sermorelin is very rapidly cleared from the plasma due to degradation. Amino acid substitutions reduce clearance and prolong the disappearance half time Soule et al. (1994).
Pharmacokinetic Properties
Empty Cell Value Units Prep. and route of admin. Reference Comments Absorption Bioavailability Distribution Volume of distribution Plasma protein binding Metabolism Plasma half-life 4.3 min Constant i.v. infusion-25 ngkg-1 min Soule et al. (1994) Bio half-life Clearance 39.7 mLkg-1 min Constant i.v. infusion-25 ngkg-1 min Soule et al. (1994) Routes of elimination
Targets-Pharmacodynamics
Sermorelin activates anterior pituitary receptors for growth hormone-releasing hormone (GHRH).
Target Name(s)
•
GHRH receptors
Therapeutics
Sermorelin is licensed as a diagnostic test for secretion of growth hormone. It is also used for the treatment of growth hormone deficiency in children. However, products containing sermorelin were withdrawn from the United States market by the manufacturer in November 2002.
Indications
Empty Cell Value Units Prep. and route of admin. Reference Comments Diagnosis of growth hormone deficiency Dosage 1 mgkg-1 Sermorelin acetate injection subcutaneously Sermorelin is administered in the morning after an overnight fast. Growth hormone therapy should be discontinued 1–2 weeks before test. A plasma GH response of 28+ 15 ngml-1 within 30 min demonstrates that the pituitary somatotrophs are intact. GH deficiency may still be the result of hypothalamic dysfunction in the presence of an intact somatotroph (http://www.bnf.org/). Treatment of growth hormone deficiency Dosage 30 mgkg-1 Sermorelin acetate injection subcutaneously Thorner et al. (1996) Sermorelin is administered at bedtime in the treatment of growth hormone deficiency.
Contraindications
Pregnancy and breast-feeding. It should be used with caution in epilepsy or in untreated hypothyroidism and in the presence of obesity, hyperglycemia, or elevated plasma fatty acids.
Adverse Effects
Occasional facial flushing and pain at injection site.
Agent-Agent Interactions
Agent name Mode of interaction Somatostatin and its analogs Reduced response to sermorelin. Glucocorticoids Reduced response to sermorelin. Insulin Increased response to sermorelin. Antithyroid drugs Reduced response to sermorelin. Antimuscarinic agents Reduced response to sermorelin.
Pre-Clinical Research
In cells cultured from rat pituitaries, sermorelin was extremely potent in stimulating the secretion of growth hormone, with a minimal effective dose of 0.4 X 10− 15 M Heiman et al. (1985).
Pharmacokinetics
No human pharmacokinetic studies appear in the literature. After IV injection in the rat, the half-life of sermorelin was around 6.2 min (Rafferty et al., 1988).
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Hormone and kinin receptor (ant)agonists
Several hormone or kinin receptor agonists and antagonists bind to MRGPRX2. These include cetrorelix (a gonadotropin-releasing hormone receptor antagonist), icatibant (a bradykinin B2 receptor antagonist), the gonadotropin-releasing hormone receptor agonist leuprorelin (also known as leuprolide), and sermorelin (a growth hormone–releasing hormone receptor agonist). All of them induced intracellular calcium influx in MRGPRX2-overexpressing cells.26 For icatibant, Alkanfari et al additionally provided evidence for MRGPRX2-dependent MC degranulation in stably transfected RBL cells.4 Subcutaneous injections of icatibant, which is used for the treatment of swelling attacks by patients with hereditary angioedema, induced MC-mediated urticarial injection site reactions184 that were attenuated by H1 antihistamines.101
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The GHRH Test
Which Analogue to Use?
The potency of the two naturally occurring analogues of GHRH, GHRH(1–40)-OH and GHRH(1–44)-NH2 and the truncated GHRH(1-29)-NH2 (sermorelin)335 has been compared and found to be equal. Of these three compounds, only sermorelin has been approved for clinical use. However, it has been withdrawn by the manufacturer and is not commercially available in the United States. Another GHRH analogue, tesamorelin, described under therapeutic uses of GHRH, has not been evaluated for diagnostic use as a GH secretagogue.
Test Procedure
The GHRH test is typically performed in the morning, after an overnight fast. GHRH is administered as an IV bolus. The dose of GHRH in both adults and children is 1 μg/kg. Serum GH levels are measured immediately before and at 15, 30, 45, and 60 minutes following the administration of GHRH.
Side Effects
Overall, side effects are uncommon following the administration of GHRH, and when they occur they are usually mild. The most frequently reported side effect is transient warmth and flushing of the face that passes within 5 minutes of administration. Other side effects reported are pain and redness at the injection site, nausea, vomiting, headache, a strange taste in the mouth, and tightness in the chest. These symptoms are transient and resolve rapidly.
The Normal GH Response to GHRH
The normal range of GH responses to GHRH in 86 children with a normal GH axis was 11.8 to 172.4 μg/L in one study, and the authors concluded that a GH response of less than 10 μg/L should be used as the diagnostic threshold for growth hormone deficiency (GHD) in children.336
The diagnostic threshold of 10 μg/L has been used in other studies utilizing the GHRH test337 and is now generally accepted in pediatric practice. This peak is similar to that used to define GHD when using the majority of stimuli in children, despite it being recognized that the different stimuli are not equal in their ability to release GH.328 Such thresholds are defined arbitrarily, despite attempts to rationalize them.338 This may reflect the fact that the diagnosis of GHD in a child depends primarily on auxologic criteria (the clinical finding of poor growth), and that the stimulation test is used to confirm the presence of GHD.
In adults, the diagnostic threshold used to identify patients with GHD is lower than that used in children. For example, a GH peak of less than 3 μg/L during an ITT is considered to be indicative of severe GHD that warrants therapy with exogenous GH, and the diagnostic cutoff for arginine stimulation is even lower.339 In adults, the GHRH test is a more potent stimulus of GH secretion, resulting in higher pulses than those seen following the ITT, the arginine test, or the glucagon test.340 This would suggest that the diagnostic cutoff for severe GHD might be higher than 3 μg/L using the GHRH test in adults, but this has not been determined.
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Introduction
Several peptide hormones are synthesized in the hypothalamus. These include oxytocin and vasopressin, which are synthesized in the paraventricular and supra-optic nuclei of the hypothalamus and stored in the posterior lobe of the pituitary gland, to which they are transported along axons in association with neurophysins. These hormones will not be considered further here. The other hormones of the hypothalamus have a key role in the regulation of the secretory activity of the anterior pituitary. They are secreted into the median eminence and transported to the anterior lobe of the pituitary via the long portal-blood vessels. Growth hormone-releasing hormone (GH-RH; somatorelin) stimulates the synthesis and secretion of growth hormone (GH; somatotropin). Thyrotropin-releasing hormone (TRH; protirelin) stimulates the secretion of thyrotropin (Cohen, 2001). Corticotrophin-releasing hormone (CRH) stimulates the secretion of corticotropin (Torpy and Jackson, 2001). Gonadotropin-releasing hormone (GnRH; gonadorelin) stimulates the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (Bremner et al., 2001). There is considerable evidence that TRH, GH-RH, and CRH have tropic effects on their target pituitary cells (Levy, 2002). On the other hand, somatostatin inhibits the secretion of GH and several other hormones (Patel, 2001). The hypothalamic hormones are normally secreted in a pulsatile manner. This pulsatile nature of secretion is physiologically important and alteration in the pulse frequency changes the secretory response of the anterior pituitary, this being best studied in relation to GnRH (Marshall et al., 2001). These peptides or their synthetic analogues are used in clinical practice either as diagnostic or therapeutic agents (Parker and Schimmer, 2001). These include analogues of GH-RH (sermorelin), gonadorelin (buserelin; histrelin; goserelin; triptorelin; nafarelin; leuprorelin) and somatostatin (lanreotide; octreotide). There are also synthetic, peptide-analogue antagonists of gonadorelin (cetrorelix; ganirelix) (Parker and Schimmer, 2001). Some of these hormones and their analogs have both therapeutic and diagnostic uses in a wide variety of conditions. Thus, gonadorelin analogs are used in assisted reproduction protocols and in advanced prostate cancer, while the somatostatin analogs lanreotide and octreotide can be used in acromegaly, as well as in the treatment of neuroendocrine tumors.
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Drugs that activate MRGPRX2
Several classes of commonly used drugs are known to activate MRGPRX2 (Table II). These include fluoroquinolone antibiotics, phenothiazines, neuromuscular blocking agents (NMBAs), hormone receptor (ant)agonists, and natural remedies.
Fluoroquinolone antibiotics
The fluoroquinolones ciprofloxacin, moxifloxacin, norfloxacin, and lomefloxacin are broad-spectrum antibiotics that inhibit prokaryotic gyrase enzymes. In 2015, McNeil et al demonstrated activation of MRGPRX2 by these fluoroquinolones in vitro, as measured by calcium mobilization assays with use of a MRGPRX2-overexpressing cell culture model and by β-hexosaminidase release of human LAD2.26 Han et al confirmed these findings,102 whereas Lansu et al questioned them.25 Hypersensitivity reactions (such as urticaria or anaphylaxis) after fluoroquinolone medication are common,95,173,174 as is pruritus.175,176 However, a few studies reported no pruritus as an adverse event in fluoroquinolone treatment.177,178 This might be due to differences in dose, application type, or study design.
Phenothiazines
Phenothiazines, in particular the world’s first antipsychotic, chlorpromazine, have a wide field of action (eg, antipsychotic, sedative, anesthetic); a broad range of molecular interactions (eg, anticholinergic, antihistaminergic, antiadrenergic); and thus, a vast variety of adverse effects such as extrapyramidal symptoms,179 hepatotoxicity,180 and weight gain.181 The phenothiazine family members chlorpromazine, thioridazine, and trifluoperazine activate MRGPRX2, as shown by calcium mobilization and degranulation assays.96 They also interact with various receptors, such as dopamine receptors.182
NMBAs
The NMBA atracurium and its isomer cisatracurium induce intracellular calcium influx and MC degranulation via MRGPRX2 in vitro.26,98 Other NMBAs such as tubocurarine and mivacurium also likely activate MRGPRX2, as they have been shown to be agonists for the murine MRGPRX2 homolog Mrgprb2.26 All 3 substances provoke wheal and flare responses following intradermal injection in humans.99 Additionally, atracurium, which is used as a paralytic NMBA, is associated with perioperative hypersensitivity reactions.183 In 2018, Navinés-Ferrer et al. demonstrated a direct link between NMBAs, MRGPRX2, and hypersensitivity reactions by using sera from patients who experienced anaphylactic reactions during anesthesia. These sera, but not control sera, induced MC degranulation, which was reduced following MRGPRX2 knockdown.169
Hormone and kinin receptor (ant)agonists
Several hormone or kinin receptor agonists and antagonists bind to MRGPRX2. These include cetrorelix (a gonadotropin-releasing hormone receptor antagonist), icatibant (a bradykinin B2 receptor antagonist), the gonadotropin-releasing hormone receptor agonist leuprorelin (also known as leuprolide), and sermorelin (a growth hormone–releasing hormone receptor agonist). All of them induced intracellular calcium influx in MRGPRX2-overexpressing cells.26 For icatibant, Alkanfari et al additionally provided evidence for MRGPRX2-dependent MC degranulation in stably transfected RBL cells.4 Subcutaneous injections of icatibant, which is used for the treatment of swelling attacks by patients with hereditary angioedema, induced MC-mediated urticarial injection site reactions184 that were attenuated by H1 antihistamines.101
Natural remedies
Many natural remedies, especially those used in traditional Chinese medicine, are ligands of MRGPRX2 and are therefore associated with anaphylactic or pseudoallergic reactions. These include praeruptorin A, schizandrin A, baicalin, the alkaloid sinomenine, the flavone glucuronides apigenin and luteolin, and salvianolic acid and its isomers.25,93,102,185 On the other hand, natural remedies are proposed to also act as MRGPRX2 antagonists (eg, quercetin186 and saikosaponin A187).
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