Gonadotropin-releasing hormone agonist (GnRH)
Triptorelin binds with high affinity to the gonadotropin-releasing hormone receptor (GnRHR) on anterior pituitary cells, which are Gq/11 protein-coupled seven-transmembrane receptors . By activating the GnRH receptor, triptorelin stimulates the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), but prolonged, continuous exposure leads to desensitization of pituitary gonadotropes, thereby suppressing sex steroid production .

Triptorelin has protection effects against tripterygium polyglycoside-induced damage to ovarian function on mouse ovarian cells [2].

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In cultured human granulosa luteinized (hGL) cells, triptorelin (1 nM and 3 nM for 48 hours) induces a slight increase in cell viability of approximately 4-10% compared to untreated controls . Although neither concentration significantly affects estradiol secretion, cultures treated with 3 nM triptorelin show lower estradiol levels than controls, with statistical significance compared to 1 nM cetrorelix-treated cells . Both concentrations of triptorelin produce a modest, non-statistically significant reduction in progesterone levels (approximately 10% reduction at 3 nM) . Additional studies demonstrate that triptorelin inhibits the growth of DU145, LNCaP, PC3 prostate cancer, and OVCAR-3 ovarian cancer cells .

Triptorelin has a protective effect on tripterygium polyglycoside-induced damage to ovarian function in female mice [2].

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In Sprague-Dawley male rats, in vivo pharmacokinetics following subcutaneous administration of triptorelin acetate silica depot formulations demonstrate 5-fold lower Cmax values compared to the reference product Pamorelin®, with comparable sustained release characteristics . The depot formulation maintains detectable triptorelin plasma concentrations throughout the 91-day study period, with testosterone plasma levels remaining below castration levels for the same duration . In clinical trials, the efficacy of triptorelin for central precocious puberty is monitored through GnRH or GnRH agonist stimulation tests, basal LH levels, or serum sex steroid concentrations .

The activity of triptorelin at the GnRH receptor is typically evaluated using radioligand binding assays in cell-free systems. Membrane preparations expressing the GnRH receptor are incubated with radiolabeled triptorelin or GnRH analogues and varying concentrations of unlabeled triptorelin. Bound and free radioligands are separated by filtration or centrifugation, and radioactivity is measured to calculate IC₅₀ or Kd values.

Human granulosa luteinized (hGL) cells are collected from women undergoing IVF treatment and seeded at a density of 20,000 live cells/well in 96-well plates. The cells are cultured in RPMI-1640 medium containing 6% fetal calf serum, 2% Ultroser G, 100 IU/ml penicillin, and 100 ng/ml streptomycin at 37°C in 5% CO₂ for 48 hours for recovery. Subsequently, cells are treated with 1 nM or 3 nM triptorelin in serum-free medium for an additional 48 hours. Cell viability is assessed using the MTT assay: 10 μl of MTT solution (5 mg/ml in sterile PBS) is added to each well, incubated for 4 hours at 37°C, followed by addition of 100 μl of solvent buffer containing 10% SDS and 50% DMF (pH 4.7), with incubation for 10-20 hours in the dark at room temperature. Optical density is measured at 595 nm. Estradiol and progesterone concentrations in culture supernatants are measured by ELISA .

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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Male Sprague-Dawley rats receive subcutaneous administration of triptorelin acetate silica microparticle depot formulations. Blood samples are collected at various time points throughout the 91-day study period. Triptorelin plasma concentrations are analyzed using ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), and testosterone concentrations are evaluated as pharmacodynamic endpoints. The pharmacokinetic and pharmacodynamic profiles of the depot formulation are compared with those of the reference product Pamorelin® LA . For central precocious puberty treatment, triptorelin is administered as a single intramuscular injection of 22.5 mg once every 24 weeks by a healthcare professional .

Absorption, Distribution and Excretion
Triptorelin is completely absorbed after intravenous injection. Excretion of triptorelin primarily occurs via the kidneys and liver. Following a single intravenous injection of 0.5 mg triptorelin in healthy males, the volume of distribution of the triptorelin peptide is 30-33 L. The total clearance of triptorelin in healthy male volunteers is 211.9 mL/min. Metabolism/Metabolites The metabolic mechanism of triptorelin in humans is not fully understood; however, its metabolism likely does not involve hepatic enzymes such as cytochrome P450. Little is known about whether and how triptorelin affects other metabolic enzymes. Triptorelin has no known metabolites. Biological Half-Life The pharmacokinetics of triptorelin follow a three-compartment model. Its estimated half-lives are 6 minutes, 45 minutes, and 3 hours.

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Triptorelin exhibits enhanced receptor binding affinity and a prolonged plasma half-life compared to native GnRH due to the D-tryptophan substitution at position 6 . The pharmacodynamic profile follows a biphasic pattern: initial stimulation of pituitary gonadotropin (LH and FSH) secretion is followed by sustained receptor downregulation, leading to suppression of gonadal sex hormone production, with testosterone levels falling to castration levels in males . A silica depot formulation of triptorelin acetate in rats demonstrates sustained release characteristics, maintaining detectable plasma concentrations throughout the 91-day study period . For central precocious puberty, triptorelin is administered as an intramuscular injection of 22.5 mg every 24 weeks .

Hepatotoxicity
Long-term use of triptorelin can cause elevated serum enzymes in 2% to 5% of patients, but the increase rarely exceeds three times the upper limit of normal (Probability score: E (unlikely to be the cause of clinically significant liver damage)). Protein binding Triptorelin does not bind to plasma proteins at clinically relevant concentrations.

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Based on pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) database (2004 Q1 to 2024 Q3), among 4,018 reports with triptorelin as the primary suspect, the most commonly reported adverse reactions include vasomotor symptoms (particularly hot flashes, >70%), sexual dysfunction, headache, mood changes, and injection site reactions . Warnings and precautions include initial rise in sex steroids due to the initial stimulatory effect, psychiatric events (such as emotional lability, irritability, anger, aggression), convulsions, severe cutaneous adverse reactions, and pseudotumor cerebri . According to FAERS data, the median time-to-onset of AEs is 132 days (IQR 36-361 days), with a bimodal distribution: 22.59% occur within the first month, and 25.07% occur after more than one year . Triptorelin is contraindicated during pregnancy or in patients with hypersensitivity to GnRH agonists or any component of the formulation .

[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 is an oligopeptide composed of pyroglutamyl, histidine, tryptophan, serine, tyrosine, D-tryptophan, leucine, arginine, prolyl, and glycine residues linked in sequence. It is an agonist analog of gonadotropin-releasing hormone (LHRH). It can be used as a LHRH agonist, an antitumor drug, and a contraceptive. Triptorelin is a synthetic decapeptide and an agonist analog of LHRH. Triptorelin is more potent than endogenous LHRH and reversibly inhibits gonadotropin secretion. With prolonged continuous administration, it can sustainably reduce LH and FSH production, as well as steroid production in the testes and ovaries. Serum testosterone concentrations may decrease to levels typically observed in surgically castrated men.
Triprelin is a gonadotropin-releasing hormone (GnRH) agonist that potently inhibits the synthesis of testosterone (in men) and estrogen (in women) and is used to treat advanced prostate cancer. The incidence of transient elevations in serum enzymes during triprelin treatment is low, but there is no conclusive evidence linking them to clinically significant cases of acute liver injury.
Triprelin is a synthetic decapeptide luteinizing hormone-releasing hormone (LHRH) agonist analog. Triptorelin is more potent than endogenous LHRH and reversibly inhibits gonadotropin secretion. With prolonged continuous administration, this drug can sustainably reduce LH and FSH production, as well as steroid production in the testes and ovaries. Serum testosterone concentrations may decrease to levels typically observed 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 permolate (active ingredient); triptorelin acetate (active ingredient).

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Drug Indications
Triptorelin is indicated for palliative treatment of advanced prostate cancer.
FDA Label
For ovulation synchronization in weaned sows for single-time, timed artificial insemination.

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Mechanism of Action
Triptorelin is a synthetic agonist analog of gonadotropin-releasing hormone (GnRH). Animal studies comparing triptorelin with natural gonadotropin-releasing hormone (GnRH) have shown that triptorelin releases 13 times more luteinizing hormone and 21 times more follicle-stimulating hormone than natural GnRH.

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Pharmacodynamics
After initial administration of triptorelin, a transient surge in follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and testosterone occurs. The timing, peak, and rate of decline of testosterone in the body depend on the administered dose. This initial surge often exacerbates early symptoms of prostate cancer, such as urethral or bladder outlet obstruction, bone pain, spinal cord injury, and hematuria. Typically, 2–4 weeks after starting treatment, FSH and LH levels steadily decline, and testosterone production decreases significantly. This eventually leads to a drop in serum testosterone levels similar to those in surgically castrated men. Ultimately, tissues and functions requiring these hormones become inactive. The effects of triptorelin are usually reversed upon discontinuation of the drug.

C64H82N18O13

1311.4487

1310.63

C, 58.61; H, 6.30; N, 19.22; O, 15.86

57773-63-4

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

25074470

H-Pyr-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2
L-pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-tryptophyl-L-leucyl-L-arginyl-L-prolyl-glycinamide

XHWSYWLRPG

Solid powder

1.5±0.1 g/cm3

1.723

-0.41

17

15

33

95

2710

9

O=C([C@]([H])(C([H])([H])C([H])([H])C([H])([H])/N=C(\N([H])[H])/N([H])[H])N([H])C([C@]([H])(C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])N([H])C([C@@]([H])(C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12)N([H])C([C@]([H])(C([H])([H])C1C([H])=C([H])C(=C([H])C=1[H])O[H])N([H])C([C@]([H])(C([H])([H])O[H])N([H])C([C@]([H])(C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12)N([H])C([C@]([H])(C([H])([H])C1=C([H])N=C([H])N1[H])N([H])C([C@]1([H])C([H])([H])C([H])([H])C(N1[H])=O)=O)=O)=O)=O)=O)=O)=O)N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(N([H])C([H])([H])C(N([H])[H])=O)=O

VXKHXGOKWPXYNA-PGBVPBMZSA-N

InChI=1S/C64H82N18O13/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)74-44/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)/t44-,45-,46-,47-,48+,49-,50-,51-,52-/m0/s1

5-Oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-tryptophyl-L-leucyl-L-arginyl-L-prolylglycinamide

Triptoreline; Arvekap; Triptorelina

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.)