GnRH/Gonadotropin-releasing hormone; Triptorelin pamoate targets and binds to the gonadotropin-releasing hormone receptor (GnRHR) on anterior pituitary gonadotropes, which are Gq/11 protein-coupled seven-transmembrane receptors . It acts as an agonist: acute administration stimulates luteinizing hormone and follicle-stimulating hormone secretion, but prolonged continuous exposure leads to inhibition of gonadotropin secretion via desensitization, resulting in sustained suppression of gonadal sex steroid production . In vitro studies show that triptorelin is 100-fold more active than native GnRH in stimulating LH release from rat pituitary cells and 20-fold more active in displacing ¹²⁵I-GnRH from pituitary receptor sites; in animal studies, triptorelin pamoate exhibits 13-fold higher LH-releasing activity and 21-fold higher FSH-releasing activity compared to native GnRH .
GnRH receptor (gonadotropin-releasing hormone receptor). Triptorelin is a GnRH agonist that binds to the GnRH receptor on pituitary gonadotrophs.

Triptorelin has protection effects against tripterygium polyglycoside-induced damage to ovarian function on mouse ovarian cells [2]. In dispersed rat pituitary cell monolayer culture models, comparative studies demonstrate that triptorelin is 100-fold more active than native GnRH in stimulating luteinizing hormone release. In receptor binding studies, triptorelin is 20-fold more active than native GnRH in displacing ¹²⁵I-GnRH from pituitary receptor sites. Additionally, in vitro studies using human peripheral blood lymphocytes cultured from females undergoing IVF treatment assessed the immunocytogenetic effects of Decapeptyl® (triptorelin pamoate), including sister chromatid exchange frequency, cell replication index, white blood cell count, phagocytic activity, and complement activity assays .

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In vitro, Triptorelin acts as a GnRH agonist, binding to the GnRH receptor on pituitary gonadotrophs. Initially, it stimulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to a temporary increase in sex hormone levels. With continued exposure, receptor downregulation leads to suppression of gonadotropin release and subsequent reduction in sex hormone production.

Triptorelin has a protective effect on tripterygium polyglycoside-induced damage to ovarian function in female mice [2]. Central Precocious Puberty: In a Phase 3 clinical trial (NCT01467882), 44 patients with central precocious puberty received triptorelin pamoate 22.5 mg via intramuscular injection once every 6 months, with a total study duration of 12 months (48 weeks), to evaluate the efficacy, safety, and pharmacokinetics of this long-acting formulation .Advanced Prostate Cancer: Triptorelin pamoate is approved under the brand name Trelstar® for the treatment of advanced prostate cancer. Upon chronic, continuous administration, it reversibly represses gonadotropin secretion, reducing serum testosterone concentrations to levels typically seen in surgically castrated men, thereby slowing or stopping the growth of cancer cells that require testosterone to grow .

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In vivo, Triptorelin functions by initially stimulating the release of LH and FSH, leading to a temporary increase in sex hormone levels. With continued administration, receptor downregulation leads to suppression of gonadotropin release and subsequent reduction in sex hormone production. Triptorelin is used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, precocious puberty, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction.

Receptor binding studies are performed using dispersed rat pituitary cells and ¹²⁵I-GnRH in competitive binding assays. The amount of bound radiolabeled ligand is measured in the presence of varying concentrations of triptorelin to calculate displacement activity and assess relative receptor affinity. Triptorelin demonstrates 20-fold higher activity in displacing ¹²⁵I-GnRH compared to native GnRH .

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Non-cell receptor binding assays are performed using membrane preparations from pituitary cells or cells expressing the GnRH receptor. Radioligand binding studies are conducted using [¹²⁵I]LHRH or [¹²⁵I]buserelin as tracers. Membranes are incubated with the radioligand and varying concentrations of Triptorelin (0.001-100 nM). Nonspecific binding is determined with excess unlabeled LHRH. After incubation at 4°C for 60-120 minutes, filtration and scintillation counting are performed. Ki values are calculated from competition curves.

In a study evaluating the immunocytogenetic effects of Decapeptyl® (triptorelin pamoate), peripheral blood samples were collected from females undergoing IVF treatment (23 treated subjects and 11 controls). Lymphocytes were cultured and examined for sister chromatid exchange frequency and cell replication index. White blood cell counts and phagocytic activity were assessed using the nitroblue tetrazolium assay following FSH and LH treatment. Macrophage nitric oxide production capacity and 50% complement hemolytic activity assays were also evaluated .

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Cellular assays are performed using pituitary cell lines (e.g., LβT2 cells) that express the GnRH receptor. Cells are treated with Triptorelin at concentrations ranging from 0.001-100 nM. LH and FSH release is measured by ELISA or RIA. Intracellular calcium mobilization is assessed using fluorescent calcium indicators (e.g., Fluo-4) as a measure of GnRH receptor activation. EC₅₀ values are calculated from dose-response curves.

For qualified, healthy SD female mice, the vaginal exfoliated cell method was used to select 30 mice with normal estrous cycle as test animals, which were randomly divided into 3 groups of 10 mice each: • Group A: blank control group, where 0.35 mL of saline was administered to the stomach once daily for 11 weeks; • Group B: tripterygium glycoside group, where 0.35 mL of tripterygium glycoside solution was administered to the stomach from the 8th day; once a day for 10 weeks; • Group C: triptolide + triptorelin group: 0.1 mg/kg daily subcutaneous injection of triptorelin injection; once a day; continuous injection for 11 weeks; from the 8th day, the triptolide solution was administered to the stomach 0.35 mL, once daily for 10 weeks. From the first day of the experiment, the general conditions of the mice were observed and recorded, including energy, activity, hair, food intake, water intake, stomach appetite, second stool, etc. The mice were weighed once a week to observe changes in body weight. The vagina exfoliation cell method, simple to operate, was used to observe the estrous cycle. After 11 weeks of treatment, the drug was stopped for 3 weeks and all mice were sacrificed. The ovaries were then obtained by laparotomy, and the ovarian wet weight was measured using an electronic analytical balance. The ovarian index was calculated by ovarian wet weight (mg) / mouse weight (g) × 100%. After weighing, the ovaries were fixed in a 4% paraformaldehyde solution for 3 days, and were routinely dehydrated, xylene-transparented, wax-impregnated, embedded, sectioned (4 µm), and operated according to the instructions of immunohistochemistry kit. Immunohistochemical average optical density (average optical) analysis method: each slice in each group randomly selected at least three positions with a 200× field of view (FoV) for photographing. When taking pictures, FoV was selected to ensure that the testing tissue fully filled the view. In addition, the background illumination of each photo was kept as consistent as possible. Image-Pro Plus 6.0 software was used to select the same brown-yellow color as the uniform standard for determining the positives of all photos. Each photo was analyzed to obtain the Integrated Optical Density (IOD) and the pixel area (AREA). The average optical density (AO) was obtained by AO = IOD/AREA. (1) The larger the AO value, the higher the positive expression level. [2]

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In animal studies, triptorelin pamoate demonstrates 13-fold higher LH-releasing activity and 21-fold higher FSH-releasing activity compared to native GnRH. In animal models of prostate cancer, chronic continuous administration leads to decreased serum testosterone concentrations. In rat studies, the depot formulation exhibits sustained drug release characteristics, maintaining therapeutic drug levels for weeks to months .

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In vivo animal studies are conducted in rodent or primate models. Triptorelin is administered via subcutaneous or intramuscular injection at doses determined from pharmacokinetic studies. Serum LH, FSH, and sex hormone levels are measured at various time points. Receptor downregulation and hormone suppression are assessed over time. Efficacy is evaluated in models of hormone-dependent cancers, endometriosis, or precocious puberty.

Triptorelin pamoate functions as a long-acting depot formulation, achieving sustained systemic exposure through conjugation of the active decapeptide with a pamoate (embonate) moiety. The formulation is administered via intramuscular injection and is designed for dosing intervals ranging from once every four weeks to once every six months. In a Phase 3 clinical study for central precocious puberty, the dosing regimen consists of 22.5 mg administered intramuscularly once every 6 months. Pharmacokinetic data demonstrate that this long-acting formulation maintains detectable and therapeutically effective drug concentrations throughout the dosing interval, enabling sustained receptor downregulation and gonadotropin suppression . The combination of triptorelin with pamoate reduces solubility, thereby slowing the release rate from the injection site and prolonging the duration of action .

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Triptorelin pamoate is a long-acting formulation that provides sustained release of triptorelin. The pamoate salt allows for slow absorption from the injection site, providing therapeutic levels for extended periods (typically 1-3 months). Triptorelin has a molecular weight appropriate for a decapeptide. The compound is administered via intramuscular or subcutaneous injection. Metabolism occurs via peptide degradation.

In an immunocytogenetic study involving 34 females (23 treated, 11 controls), the triptorelin pamoate-treated group showed significantly higher white blood cell counts on the day of ovum pick-up compared to controls. The treated group also demonstrated significantly higher sister chromatid exchange frequencies following gonadotropin administration compared to controls. However, the 50% complement hemolytic activity assay indicated that Decapeptyl® lacks significant potential to affect the complement system. Macrophage nitric oxide production capacity showed no significant changes compared to controls .

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Triptorelin is generally well tolerated. Common adverse effects include hot flashes, sweating, and injection site reactions. Long-term use may lead to bone density loss and increased risk of osteoporosis. The compound is contraindicated during pregnancy and in patients with known hypersensitivity to GnRH analogs.

[1]. Efficacy and safety of triptorelin 6-month formulation in patients with central precocious puberty.2016 Nov 1;29(11):1241-1248.
[2]. www.ejgo.net/articles/10.31083/j.ejgo.2021.02.2299

Triptorelin pamoate is the pamoate salt of triptorelin, a synthetic decapeptide luteinizing hormone-releasing hormone (LHRH) agonist analog. Triptorelin is more potent than endogenous LHRH and reversibly inhibits gonadotropin secretion with prolonged administration. With continued long-term administration, a sustained decrease in LH, FSH, and testicular and ovarian steroid production can be observed. Serum testosterone concentrations may decrease to levels typically seen in surgically castrated men. (NCI04)
A potent synthetic long-acting gonadotropin-releasing hormone agonist with its 6th residue replaced by D-tryptophan.
See also: Triptorelin pamoate (note moved to).

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Triptorelin pamoate is a long-acting GnRH agonist used for the treatment of advanced prostate cancer, breast cancer, precocious puberty, endometriosis, and uterine fibroids. It is a synthetic decapeptide with D-tryptophan substitution at residue 6. The pamoate salt provides sustained release for 1-3 months. Triptorelin is available as a prescription medication in many countries. The compound is on the WHO Model List of Essential Medicines.

C87H98N18O19

1699.85

1698.725

C, 61.47; H, 5.81; N, 14.83; O, 17.88

124508-66-3

140194-24-7 (acetate);57773-63-4;124508-66-3 (pamoate);2240176-35-4 (TFA);

25074469

Solid powder

21

21

37

124

3280

9

N.NC(NCCCC(C(CN1CCCC1C(NCC(=O)N)=O)=O)NC(C(NC(C(CC1=CCC2=CC=CC=C12)NC(C(NC(C(NC(C(NC(C(CC(C1CCC(=O)N1)=O)CC1=CN=CN1)=O)CCC1=CC=CC=C1NC=C)=O)CO)=O)CC1=CC=C(O)C=C1)=O)=O)CC(C)C)=O)=N.OC(C1=CC2=CC=CC=C2C(CC2=C(O)C(C(=O)O)=CC3=CC=CC=C23)=C1O)=O

ZBVJFYPGLGEMIN-OYLNGHKZSA-N

InChI=1S/C64H82N18O13.C23H16O6/c1-34(2)23-46(56(88)75-45(13-7-21-69-64(66)67)63(95)82-22-8-14-52(82)62(94)72-31-53(65)85)76-58(90)48(25-36-28-70-42-11-5-3-9-40(36)42)78-57(89)47(24-35-15-17-39(84)18-16-35)77-61(93)51(32-83)81-59(91)49(26-37-29-71-43-12-6-4-10-41(37)43)79-60(92)50(27-38-30-68-33-73-38)80-55(87)44-19-20-54(86)74-4424-20-16(14-7-3-1-5-12(14)9-18(20)22(26)27)11-17-15-8-4-2-6-13(15)10-19(21(17)25)23(28)29/h3-6,9-12,15-18,28-30,33-34,44-52,70-71,83-84H,7-8,13-14,19-27,31-32H2,1-2H3,(H2,65,85)(H,68,73)(H,72,94)(H,74,86)(H,75,88)(H,76,90)(H,77,93)(H,78,89)(H,79,92)(H,80,87)(H,81,91)(H4,66,67,69)1-10,24-25H,11H2,(H,26,27)(H,28,29)/t44-,45-,46-,47-,48+,49-,50-,51-,52-/m0./s1

(S)-1-((3S,6S,9S,12S,15R,18S,21S)-3-((1H-imidazol-5-yl)methyl)-6,15-bis((1H-indol-3-yl)methyl)-21-(3-((diaminomethylene)amino)propyl)-12-(4-hydroxybenzyl)-9-(hydroxymethyl)-18-isobutyl-1,4,7,10,13,16,19-heptaoxo-1-((S)-5-oxopyrrolidin-2-yl)-2,5,8,11,14,17,20-heptaazadocosan-22-oyl)-N-(2-amino-2-oxoethyl)pyrrolidine-2-carboxamide 4,4'-methylenebis(3-hydroxy-2-naphthoate)

AY25650; Wy42462; CL118532; AY-25650; Wy-42462; CL-118532; AY 25650; CL 118532; Wy4 2462; Triptorelin; D-Trp-6-LH-RH Trelstar; Depot. Decapeptyl; Decapeptyl; Depot; Decapeptyl; LP Decapeptyl; Trimestral Embonate.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: > 10mM

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)