Triptorelin associated adverse events evaluated using FAERS pharmacovigilance data

A total of 21,838,627 reports were extracted from the FAERS database during the study period. After excluding duplicates, 4,018 case reports identified triptorelin as the primary suspect (PS) drug, with 10,117 associated adverse events (AEs). The clinical characteristics of these AEs are summarized in Table  2 . The gender distribution was nearly balanced, with females accounting for 45.55%(1830 cases) and males for 45.84%(1842 cases). Age-wise, patients over 64 years (21.65%) and under 18 years (18.22%) represented a higher proportion compared to those aged 18–64 years (10.38%). Prostate cancer was the most frequently reported indication (30.44%), followed by precocious puberty (5.82%). Geographically, the US reported the highest number of AEs (55.40%), followed by France (9.68%), the Netherlands (7.17%), Canada (3.93%), and Switzerland (2.81%). Consumers were the primary reporting source (49.98%). AE outcomes were categorized according to FDA criteria(e.g.,hospitalization, death). While disproportionality analysis does not assess clinical severity, our data revealed notable proportions of serious outcomes: other serious medical events (22.22%) and hospitalization (16.90%) were most prevalent, with death and life-threatening events reported in 8.74% and 1.47% of cases, respectively. Crucially, the elevated proportion of fatal outcomes(8.74%) likely reflects the progression of underlying malignancies - particularly advanced prostate cancer, which constituted 84.3% of indications in this cohort - rather than attributable solely to triptorelin exposure. The annual volume of triptorelin-associated AE reports increased over time, peaking in 2019(17.87%), followed by 2021 (14.46%), 2023 (11.45%), 2020 (11.30%), 2022 (11.15%), and the third quarter of 2024(11.30%). Fig. 1 Flowchart of Triptorelin-Related AE Selection from FAERS. ( DEMO demographic and administrative information, DRUG drug information, REAC preferred terminology for adverse event, PS primary suspect drug). Flowchart of Triptorelin-Related AE Selection from FAERS. ( DEMO demographic and administrative information, DRUG drug information, REAC preferred terminology for adverse event, PS primary suspect drug). Table 1 Four key algorithms for evaluating potential associations between Triptorelin and aes. Algorithms Equation Criteria ROR ROR = ad/bc lower limit of 95% CI > 1, N  ≥ 3 95%CI = e ln(ROR)±1.96(1/a+1/b+1/c+1/d)^0.5 PRR PRR=(a(c + d))/(c(a + b)) PRR ≥ 2, χ 2  ≥ 4, N  ≥ 3 χ 2 = [(ad − bc)^2](a + b + c + d)/[(a + b)(c + d)(a + c)(b + d)] BCPNN IC = log 2 a(a + b + c + d)(a + c)(a + b) IC 025  > 0 IC 025  = e ln(IC)−1.96(1/a+1/b+1/c+1/d)^0.5 MGPS EBGM = a(a + b + c + d)/((a + c)/(a + b)) EBGM05 > 2, N  > 0 EBGM05 = e ln(EBGM)−1.64(1/a+1/b+1/c+1/d)^0.5 Four key algorithms for evaluating potential associations between Triptorelin and aes. a : the number of reports with suspect adverse events (AEs) of the suspect drug; b : the number of reports with all other AEs of the suspect drug; c : the number of reports with the suspect AEs of all other drugs; d : the number of reports with all other AEs of all other drugs; ROR : reporting odds ratio; CI : confidence interval; N : the number of co-occurrences; PRR : proportional reporting ratio; χ 2 : chi-squared; BCPNN : Bayesian confidence propagation neural network; IC : information component; IC025 : the lower limit of the 95% two-sided CI of the IC; MGPS : multi-item gamma Poisson shrinker; EBGM : empirical Bayesian geometric mean; EBGM05 : the lower 95% one-sided CI of EBGM. Table 2 Clinical features of Triptorelin reports in the FAERS (January 2004 to September 2024). Characteristics Case number ( n ) Case proportion (%) All cases 4018 Gender Male 1842 45.84 Female 1830 45.55 Unknown 346 8.61 Age(year)  64 870 21.65 Unknown 1999 49.75 Weight (kg) 100 kg 32 5.77 Unknown 3706 92.23 Reported Person Consumer 2008 49.98 Health Professional 588 14.63 Physician 642 15.98 Other Health Professional 479 11.92 Pharmacist 183 4.55 Unknown 118 2.94 Reported Countries(Top five) USA 2226 55.40 France 389 9.68 Netherlands 288 7.17 Canada 158 3.93 Switzerland 113 2.81 Indications(Top five) Prostate Cancer 1223 30.44 Precocious Puberty 234 5.82 Gender Dysphoria 128 3.19 Breast Cancer 116 2.89 Trans-sexualism 50 1.24 Outcome Death 351 8.74 Life-threatening 59 1.47 Hospitalization 679 16.90 Disability 73 1.82 Other serious Outcome 893 22.22 Clinical features of Triptorelin reports in the FAERS (January 2004 to September 2024). Cases with incomplete dose, frequency, or indication information were excluded. The signal strength reports of triptorelin at the System Organ Class (SOC) level are presented in Table  3 . Statistical analysis identified 27 organ systems with disproportional reporting. The SOCs meeting all four algorithm criteria and showing significant association with triptorelin were reproductive system and breast disorders (SOC: 10038604), and product issues (SOC: 10077536). Other notable SOCs meeting two criteria included endocrine disorders (SOC: 10014698), injury/poisoning/procedural complications (SOC: 10022117), psychiatric disorders (SOC: 10037175), and vascular disorders (SOC: 10047065). Given that FAERS encompasses all medical and health-related PTs, it may also incorporate some non-drug-related AE signals that could be potentially related to disease progression or other factors. Non-drug-related AE signals, including congenital/familial/genetic disorders (SOC: 10010331), general disorders and administration site conditions (SOC: 10018065), injury/poisoning/procedural complications (SOC: 10022117), pregnancy/puerperium/perinatal conditions (SOC: 10036585), product issues (SOC: 10077536), surgical and medical procedures (SOC: 10042613), neoplasms benign/malignant/unspecified (including cysts and polyps) (SOC: 10029104) were excluded from further analyses to focus on triptorelin-specific effects. Using four pharmacovigilance algorithms (ROR, PRR, BCPNN, and MGPS), we identified 73 statistically significant Preferred Terms(PTs) at the MedDRA ® level(Table  4 ). Label-listed events such as psychiatric, nervous system, investigations, musculoskeletal and connective tissue, reproductive system and breast, skin and subcutaneous tissue, vascular, metabolism and nutrition disorder were commonly reported. In this study, events such as mood altered (PT: 10027940), anger (PT: 10002368), weight increased (PT: 10047899), hormone level abnormal (PT: 10061210), blood testosterone increased (PT: 10005815), bone pain (PT: 10006002), osteoporosis (PT: 10031282), muscle atrophy (PT: 10028289), vaginal haemorrhage (PT: 10046910), ovarian hyperstimulation syndrome (PT: 10033266), testicular atrophy (PT: 10043298), dyspareunia (PT: 10013941), acne (PT: 10000496), hot flush (PT: 10060800), increased appetite (PT: 10021654) were present, consistent with the instructions and medication warnings. During the analysis of triptorelin, unexpected statistically significant signals were discovered as shown in Table  3 , including but not limited to the following PTs: personality change (PT: 10034719), behaviour disorder (PT: 10004207), defiant behaviour (PT: 10077244), dementia alzheimer’s type (PT: 10012271), polyneuropathy (PT: 10036105), spinal cord compression (PT: 10041549), prostatic specific antigen increased (PT: 10036975), body height increased (PT: 10056813), blood testosterone decreased (PT: 10005814), growth accelerated (PT: 10018746), epiphyses premature fusion (PT: 10015078), growth retardation (PT: 10053759), skin odour abnormal (PT: 10040904), ophthalmoplegia (PT: 10030875), choroidal neovascularisation (PT: 10060823), acute coronary syndrome (PT: 10051592), hepatitis fulminant (PT: 10019772), pituitary apoplexy (PT: 10056447), pituitary haemorrhage (PT: 10049760), etc., which are not currently listed in the product label. Among the 73 statisticlly significant PTs, 36 signals demonstrated strong statistical strength (IC025 > 3.0) and 23 showed medium strength (1.5 < IC025 ≤ 3.0). The strong signal included both expected effects consistent with triptorelin’s known safety profile, such as mood altered (PT: 10006002), hormone level abnormal (PT: 10061210), blood testosterone increased (PT: 10005815), epiphysiolysis (PT: 10015079), ovarian hyperstimulation syndrome (PT: 10033266), testicular atrophy (PT: 10043298), and breast atrophy (PT: 10006179). Notably, several labeled adverse events (e.g., depression, anxiety, headache) failed to meet statistical significance thresholds in our analysis despite clinical reports, highlighting the hypothesis-generating nature of this pharmacovigilance approach. Table 3 Statistical signal strength of AEs reported with Triptorelin at the system organ class (SOC) level. System organ class(SOC) Triptorelin cases reporting SOC ROR (95% two sided Cl) PRR (χ 2 ) IC (IC 025) EBGM (EBGM 05) Reproductive System And Breast Disorders 500 6.22(5.69–6.81) * 5.96(2080.21) * 2.57(2.44) * 5.96(5.53) * Product Issues 666 4.39(4.06–4.75) * 4.17(1627.51) * 2.06(1.94) * 4.16(3.90) * Endocrine Disorders 51 1.97(1.50–2.60) * 1.97(24.37) 0.98(0.58) * 1.97(1.56) Injury, Poisoning And Procedural Complications 1542 1.73(1.64–1.83) * 1.62(401.66) 0.69(0.62) * 1.62(1.55) Psychiatric Disorders 922 1.64(1.54–1.76) * 1.58(210.86) 0.66(0.56) * 1.58(1.50) Vascular Disorders 285 1.30(1.16–1.47) * 1.29(19.43) 0.37(0.20) * 1.29(1.17) Musculoskeletal And Connective Tissue Disorders 570 1.06(0.98–1.16) 1.06(1.92) 0.08(−0.04) 1.06(0.99) Skin And Subcutaneous Tissue Disorders 493 0.89(0.82–1.34) 0.90(5.86) −0.15(−0.29) 0.90(0.83) Nervous System Disorders 784 0.90(0.83–0.97) 0.91(8.42) −0.14(−0.25) 0.91(0.85) Metabolism And Nutrition Disorders 172 0.78(0.67–0.91) 0.78(10.38) −0.35(−0.57) 0.78(0.69) General Disorders And Administration Site Conditions 1454 0.79(0.75–0.83) 0.82(70.79) −0.29(−0.37) 0.82(0.78) Gastrointestinal Disorders 454 0.50(0.45–0.55) 0.52(219.31) −0.94(−1.08) 0.52(0.48) Investigations 610 0.96(0.89–1.04) 0.96(0.85) −0.05(−0.17) 0.96(0.90) Respiratory, Thoracic And Mediastinal Disorders 205 0.41(0.36–0.47) 0.42(171.58) −1.25(−1.45) 0.42(0.37) Neoplasms Benign, Malignant And Unspecified (Incl Cysts And Polyps) 241 0.89(0.78–1.01) 0.89(3.37) −0.17(−0.36) 0.89(0.80) Eye Disorders 131 0.64(0.54–0.76) 0.64(26.99) −0.64(−0.90) 0.64(0.55) Ear And Labyrinth Disorders 44 1.00(0.74–1.34) 1.00(0.00) 0.00(−0.43) 1.00(0.78) Hepatobiliary Disorders 48 0.51(0.39–0.68) 0.51(22.15) −0.96(−1.37) 0.51(0.41) Infections And Infestations 272 0.49(0.44–0.56) 0.51(138.36) −0.98(−1.16) 0.51(0.46) Surgical And Medical Procedures 138 1.00(0.85–1.18) 1.00(0.00) 0.00(−0.24) 1.00(0.87) Cardiac Disorders 125 0.45(0.38–0.54) 0.46(80.69) −1.12(−1.37) 0.46(0.40) Blood And Lymphatic System Disorders 118 0.68(0.56–0.81) 0.68(18.24) −0.56(−0.82) 0.68(0.58) Renal And Urinary Disorders 140 0.74(0.63–0.88) 0.74(12.48) −0.43(−0.67) 0.74(0.65) Immune System Disorders 51 0.45(0.34–0.59) 0.45(34.60) −1.15(−1.55) 0.45(0.36) Social Circumstances 53 1.20(0.92–1.57) 1.20(1.75) 0.26(−0.13) 1.20(0.96) Pregnancy, Puerperium And Perinatal Conditions 19 0.43(0.28–0.68) 0.43(14.20) −1.21(−1.85) 0.43(0.30) Congenital, Familial And Genetic Disorders 29 0.93(0.65–1.34) 0.93(0.15) −0.10(−0.63) 0.93(0.69) Indicates statistically significant signals in algorithm; ROR , reporting odds ratio, CI , confidence interval, PRR , proportional reporting ratio, χ2 , chi-squared, IC , information component, IC 025 , the lower limit of 95% CI of the IC, EBGM , empirical Bayesian geometric mean, EBGM 05 , the lower limit of 95% CI of EBGM Statistical signal strength of AEs reported with Triptorelin at the system organ class (SOC) level. Indicates statistically significant signals in algorithm; ROR , reporting odds ratio, CI , confidence interval, PRR , proportional reporting ratio, χ2 , chi-squared, IC , information component, IC 025 , the lower limit of 95% CI of the IC, EBGM , empirical Bayesian geometric mean, EBGM 05 , the lower limit of 95% CI of EBGM Table 4 Statistical signal intensity of Triptorelin AE reports at the preferred term (PT) level. SOC Preferred terms(PT) Triptorelin cases reporting PT ROR (95% two sided Cl) PRR (χ2) IC (IC 025) EBGM (EBGM 05) Psychiatric Disorders Mood Altered 107 23.76(19.63–28.76) 23.52(2298.00) 4.55(4.27) a 23.42(19.96) Mood Swings 89 16.31(13.24–20.11) 16.18(1264.28) 4.01(3.71) a 16.13(13.54) Depression 62 1.57(1.22–2.01) 1.56(12.59) 0.64(0.28) 1.56(1.27) Aggression 54 6.24(4.77–8.15) 6.21(236.00) 2.63(2.24) b 6.20(4.96) Emotional Disorder 54 10.38(7.94–13.56) 10.33(454.13) 3.37(2.98) b 10.31(8.24) Affect Lability 49 29.36(22.16–38.90) 29.22(1328.30) 4.86(4.45) a 29.06(22.97) Irritability 47 4.53(3.40–6.04) 4.52(128.68) 2.17(1.76) b 4.51(3.55) Anxiety 46 0.94(0.70–1.25) 0.94(0.18) −0.09(−0.51) 0.94(0.74) Insomnia 37 0.81(0.59–1.12) 0.81(1.66) −0.30(−0.77) 0.81(0.62) Abnormal Behaviour 32 4.54(3.20–6.42) 4.52(87.83) 2.18(1.67) b 4.52(3.38) Suicidal Ideation 27 1.73(1.19–2.53) 1.73(8.34) 0.79(0.24) 1.73(1.26) Anger 22 3.72(2.45–5.66) 3.72(43.71) 1.89(1.29) 3.72(2.62) Personality Change * 20 12.14(7.82–18.83) 12.12(203.54) 3.60(2.96) b 12.09(8.37) Behaviour Disorder * 9 11.62(6.04–22.36) 11.62(87.13) 3.54(2.62) b 11.59(6.70) Enuresis 7 10.34(4.93–21.72) 10.34(58.93) 3.37(2.35) b 10.32(5.55) Defiant Behaviour * 5 122.33(50.39-296.97) 122.27(587.75) 6.90(5.71) a 119.52(56.90) Nervous System Disorders Headache 137 1.29(1.09–1.53) 1.29(9.06) 0.37(0.12) 1.29(1.12) Dementia Alzheimer’S Type * 106 68.90(56.83–83.54) 68.19(6929.07) 6.07(5.79) a 67.33(57.31) Dizziness 88 1.05(0.85–1.29) 1.05(0.18) 0.06(−0.24) 1.05(0.88) Paraesthesia 26 0.96(0.65–1.41) 0.96(0.05) −0.06(−0.62) 0.96(0.69) Polyneuropathy * 9 4.64(2.41–8.92) 4.63(25.62) 2.21(1.30) 4.63(2.68) Spinal Cord Compression * 4 5.93(2.22–15.82) 5.93(16.37) 2.57(1.27) 5.92(2.61) Investigations Weight Increased 153 4.18(3.56–4.90) 4.13(364.22) 2.05(1.81) b 4.13(3.61) Prostatic Specific Antigen Increased * 45 19.13(14.27–25.65) 19.05(766.95) 4.25(3.82) a 18.98(14.85) Hormone Level Abnormal 23 29.11(19.32–43.88) 29.05(619.54) 4.85(4.26) a 28.89(20.50) Blood Pressure Systolic Increased 23 6.94(4.61–10.45) 6.92(116.45) 2.79(2.20) b 6.92(4.91) Blood Testosterone Increased 14 38.86(22.96–65.76) 38.80(511.84) 5.27(4.52) a 38.53(24.81) Body Height Increased * 9 140.12(72.26-271.73) 140.00(1209.87) 7.09(6.17) a 136.40(78.37) Blood Luteinising Hormone Increased 8 193.10(95.33-391.13) 192.95(1473.55) 7.54(6.56) a 186.15(103.13) Blood Testosterone Decreased * 7 5.75(2.74–12.07) 5.75(27.43) 2.52(1.50) 5.74(3.09) Blood Luteinising Hormone Decreased 6 206.31(91.24-466.53) 206.19(1178.93) 7.63(6.52) a 198.45(100.26) Blood Testosterone Abnormal 5 26.49(11.00-63.79) 26.47(121.95) 4.72(3.54) a 26.35(12.63) Blood Pressure Diastolic Increased 5 6.49(2.70-15.61) 6.49(23.19) 2.70(1.52) b 6.48(3.11) Prostatic Specific Antigen Decreased 4 64.94(24.22–174.10) 64.91(248.64) 6.00(4.70) a 64.13(28.10) Musculoskeletal And Connective Tissue Disorders Arthralgia 62 0.90(0.70–1.15) 0.90(0.71) −0.15(−0.52) 0.90(0.73) Back Pain 49 1.24(0.93–1.64) 1.24(2.23) 0.31(−0.10) 1.24(0.98) Pain In Extremity 49 0.96(0.72–1.27) 0.96(0.09) −0.06(−0.47) 0.96(0.76) Bone Pain 33 3.32(2.36–4.68) 3.31(53.34) 1.73(1.23) 3.31(2.49) Growth Accelerated * 32 1035.48(708.50-1513.37) 1032.21(27556.88) 9.75(9.21) a 862.98(628.21) Epiphyses Premature Fusion * 28 615.11(415.67-910.24) 613.41(15331.03) 9.10(8.54) a 549.43(395.82) Osteoporosis 27 3.84(2.63–5.60) 3.83(56.52) 1.94(1.39) 3.83(2.79) Osteopenia 14 5.28(3.13–8.93) 5.28(48.49) 2.40(1.65) b 5.27(3.40) Muscle Atrophy 11 5.44(3.01–9.82) 5.43(39.73) 2.44(1.61) b 5.43(3.31) Growth Retardation * 11 21.81(12.06–39.44) 21.78(217.24) 4.44(3.60) a 21.70(13.22) Epiphysiolysis 7 171.30(80.67-363.75) 171.18(1146.99) 7.37(6.33) a 165.82(88.31) Polyarthritis 5 5.91(2.46–14.21) 5.91(20.37) 2.56(1.38) 5.90(2.83) Growth Disorder 5 124.07(51.10-301.22) 124.00(596.01) 6.92(5.73) a 121.17(57.68) Pathological Fracture 5 5.83(2.42–14.01) 5.83(19.96) 2.54(1.36) 5.82(2.79) Reproductive System And Breast Disorders Vaginal Haemorrhage 119 16.10(13.44–19.30) 15.93(1660.90) 3.99(3.72) a 15.88(13.65) Breast Enlargement 75 132.29(105.11-166.49) 131.31(9463.33) 7.00(6.67) a 128.14(105.71) Ovarian Hyperstimulation Syndrome 65 174.42(136.13-223.48) 173.31(10780.30) 7.39(7.03) a 167.81(136.38) Vaginal Discharge 15 8.65(5.21–14.36) 8.64(101.20) 3.11(2.39) b 8.63(5.65) Dysmenorrhoea 15 6.94(4.18–11.52) 6.93(76.01) 2.79(2.07) b 6.92(4.53) Heavy Menstrual Bleeding 14 15.73(9.31–26.59) 15.71(192.30) 3.97(3.22) a 15.67(10.10) Menstrual Disorder 11 8.00(4.42–14.45) 7.99(67.16) 3.00(2.16) b 7.98(4.86) Breast Pain 10 5.41(2.91–10.07) 5.41(35.91) 2.43(1.56) b 5.40(3.22) Ovarian Cyst 8 4.56(2.28–9.11) 4.55(22.16) 2.19(1.22) 4.55(2.55) Breast Swelling 7 14.86(7.08–31.22) 14.85(90.19) 3.89(2.87) b 14.81(7.96) Intermenstrual Bleeding 7 13.59(6.47–28.55) 13.59(81.41) 3.76(2.74) b 13.55(7.28) Dyspareunia 6 8.26(3.71–18.40) 8.25(38.19) 3.04(1.95) b 8.24(4.22) Ovarian Enlargement 5 75.36(31.17-182.24) 75.33(361.52) 6.21(5.03) a 74.28(35.48) Testicular Atrophy 4 27.15(10.16–72.53) 27.14(100.18) 4.76(3.46) a 27.00(11.87) Testicular Swelling 4 18.57(6.96–49.57) 18.56(66.23) 4.21(2.92) b 18.50(8.14) Spontaneous Penile Erection 4 37.17(13.90-99.41) 37.16(139.75) 5.21(3.91)a 36.90(16.20) Breast Atrophy 4 106.26(39.48-285.98) 106.22(408.66) 6.70(5.40) a 104.13(45.48) Skin And Subcutaneous Tissue Disorders Acne 82 6.20(4.99–7.70) 6.15(354.05) 2.62(2.30)b 6.15(5.13) Hair Growth Abnormal * 58 49.69(38.34–64.40) 49.41(2725.61) 5.61(5.23)a 48.96(39.41) Rash 46 0.65(0.48–0.86) 0.65(8.90) −0.63(−1.05) 0.65(0.51) Hyperhidrosis 38 1.72(1.25–2.36) 1.72(11.36) 0.78(0.32) 1.72(1.31) Pruritus 27 0.46(0.31–0.66) 0.46(17.56) −1.13(−1.68) 0.46(0.33) Skin Odour Abnormal * 22 33.30(21.89–50.66) 33.23(683.44) 5.05(4.44) a 33.03(23.25) Hypertrichosis * 15 45.58(27.41–75.79) 45.51(647.38) 5.50(4.77) a 45.13(29.49) Seborrhoea 5 7.71(3.21–18.54) 7.71(29.14) 2.94(1.77) b 7.70(3.69) Cutaneous Vasculitis 4 8.04(3.01–21.43) 8.03(24.59) 3.00(1.71) b 8.02(3.53) Gastrointestinal Disorders Nausea 73 0.55(0.44–0.69) 0.55(26.94) −0.86(−1.19) 0.55(0.46) Vomiting 65 0.83(0.65–1.06) 0.83(2.20) −0.26(−0.62) 0.83(0.68) Abdominal Pain 54 1.39(1.06–1.81) 1.38(5.77) 0.47(0.08) 1.38(1.11) Ascites 19 3.80(2.42–5.97) 3.80(39.15) 1.92(1.28) 3.80(2.60) Vascular Disorders Hot Flush 133 11.27(9.49–13.37) 11.13(1225.34) 3.47(3.22) a 11.11(9.63) Hypertension 36 1.01(0.73–1.40) 1.01(0.00) 0.01(−0.47) 1.01(0.77) Hypotension 14 0.41(0.24–0.69) 0.41(11.78) −1.28(−2.02) 0.41(0.27) Hypertensive Crisis 9 4.70(2.45–9.05) 4.70(26.21) 2.23(1.32) 4.70(2.72) Respiratory, Thoracic And Mediastinal Disorders Dyspnoea 41 0.43(0.31–0.58) 0.43(31.42) −1.22(−1.67) 0.43(0.33) Cough 28 0.60(0.42–0.87) 0.60(7.30) −0.73(−1.26) 0.60(0.44) Metabolism And Nutrition Disorders Increased Appetite 47 16.32(12.25–21.75) 16.25(670.92) 4.02(3.60) a 16.21(12.75) Eye Disorders Vision Blurred 25 1.10(0.74–1.63) 1.10(0.22) 0.13(−0.43) 1.10(0.79) Visual Impairment 9 0.45(0.23–0.86) 0.45(6.15) −1.16(−2.07) 0.45(0.26) Ophthalmoplegia * 7 27.71(13.18–58.26) 27.69(179.17) 4.78(3.76) a 27.55(14.80) Choroidal Neovascularisation * 4 29.22(10.94–78.09) 29.21(108.38) 4.86(3.57) a 29.05(12.77) Renal And Urinary Disorders Acute Kidney Injury 14 0.56(0.33–0.95) 0.56(4.84) −0.84(−1.58) 0.56(0.36) Hydronephrosis 6 4.76(2.14–10.61) 4.76(17.81) 2.25(1.16) 4.76(2.43) Calculus Urinary 6 22.43(10.06–50.03) 22.42(122.28) 4.48(3.39) a 22.33(11.41) Cardiac Disorders Acute Coronary Syndrome * 8 5.42(2.71–10.85) 5.42(28.80) 2.44(1.47) 5.41(3.03) Blood And Lymphatic System Disorders Anaemia 34 1.04(0.74–1.46) 1.04(0.05) 0.06(−0.43) 1.04(0.78) Thrombocytopenia 16 0.86(0.52–1.40) 0.86(0.39) −0.22(−0.93) 0.86(0.57) Hepatobiliary Disorders Hepatitis 6 1.40(0.63–3.12) 1.40(0.69) 0.49(−0.60) 1.40(0.72) Hepatitis Fulminant * 4 7.83(2.94–20.89) 7.83(23.80) 2.97(1.68) b 7.82(3.44) Immune System Disorders Hypersensitivity 25 0.80(0.54–1.19) 0.80(1.24) −0.32(−0.89) 0.80(0.58) Ear And Labyrinth Disorders Vertigo 14 1.34(0.80–2.27) 1.34(1.22) 0.42(−0.32) 1.34(0.87) Endocrine Disorders Precocious Puberty 11 113.30(62.33-205.96) 113.18(1197.34) 6.79(5.95) a 110.82(67.21) Pituitary Apoplexy * 7 281.15(131.40-601.52) 280.95(1853.64) 8.06(7.01) a 266.75(141.16) Pituitary Haemorrhage * 4 69.44(25.89-186.24) 69.41(266.19) 6.10(4.80) a 68.52(30.01) Emerging findings of statistically significant associations between Triptorelin and AEs from FAERS. a , IC025 > 3.0, it indicates a strong signal; b ,1.5 < IC025 ≤ 3.0, it indicates a signal of medium statistical streng t ; ROR , reporting odds ratio, CI , confidence interval, PRR , proportional reporting ratio, χ2 ,chi-squared, IC , information component, IC 025 , the lower limit of 95% CI of the IC, EBGM , empirical Bayesian geometric mean, EBGM 05 ,the lower limit of 95% CI of EBGM. Statistical signal intensity of Triptorelin AE reports at the preferred term (PT) level. Emerging findings of statistically significant associations between Triptorelin and AEs from FAERS. a , IC025 > 3.0, it indicates a strong signal; b ,1.5 < IC025 ≤ 3.0, it indicates a signal of medium statistical streng t ; ROR , reporting odds ratio, CI , confidence interval, PRR , proportional reporting ratio, χ2 ,chi-squared, IC , information component, IC 025 , the lower limit of 95% CI of the IC, EBGM , empirical Bayesian geometric mean, EBGM 05 ,the lower limit of 95% CI of EBGM. The onset times of AEs associated with triptorelin were retrieved and analyzed from the FAERS database. After excluding reports with missing or incorrect onset times, 726 AEs with valid data were analyzed. The median onset time was 132 days(IQR:36–361 days). As shown in FIGURE 2 , most AEs occurred within the first month(22.59%) or after one year (25.07%). Although the number of AEs declined over time, 70 AEs (9.64%) emerged in the second month and 68 AEs (9.37%) in the third month. Notably, 17.49% and 15.84% of cases emerged after three and six months, respectively. TTO analysis was limited to 18% (726/4018) of eligible reports due to missing/invalid dates. The high proportion of missing TTO data (82%) may disproportionately affect detection of early-onset events, limiting conclusions about temporal risk patterns. Fig. 2 Time-to-onset analysis for triptorelin-related singals via weibull distribution test. Time-to-onset analysis for triptorelin-related singals via weibull distribution test. In the assessment of the Weibull Shape Parameter analysis (Table  5 ), the shape parameter (β) was computed as 0.67, and the upper bound of its 95% confidence interval (CI) was 0.71. A β value less than 1 implies that the hazard rate (or instantaneous risk) of AE reporting was presumed to initially be higher and decline over time, signifying an early failure pattern. Table 5 Time-to-onset analysis for triptorelin-related signals via Weibull distribution test. Cases TTO (days) Weibull distribution Failure type Scale parameter Shape parameter n Media (IQR) Min-Max α 95% CI β 95% CI 726 132(36-361) 1-3009 233.79 207.07-260.50 0.67 0.63-0.71 Early failure Time-to-onset analysis for triptorelin-related signals via Weibull distribution test. FIGURE 3 displays age-stratified disproportionality signals. In the  64 group, likely due to underlying malignancies. Additionally, upon analyzing the top 10 AEs in each subgroup, it was observed that vaginal haemorrhage and weight increased were exclusive to the  64 subgroup. Gastrointestinal events were more common in other two age groups (18–64 and > 64). At the PT level, 36 signals showed gender-disproportional AE occurrence (FIGURE 4 ). In females, AEs with strong statistical signals more likely to occur comprised upper abdominal pain, crying, abnormal hormone level, increased appetite, premature epiphyses fusion, headache, psychiatric disorders, acne, abnormal hair growth, and abnormal skin odor. In contrast, frequently reported AEs in males included anemia, thrombocytopenia, fatigue, asthenia, disease progression, fall, arthralgia, back pain, myalgia, muscular weakness, osteoporosis, bone metastases, cerebrovascular accident, hyperhidrosis, and hot flush.

For a comprehensive assessment of triptorelin’s post-marketing safety, a retrospective pharmacovigilance study was carried out using data from the FDA Adverse Event Reporting System (FAERS) (accessible at https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE- FAERS.html) spanning January 2004 to September 2024(2004Q1-2024Q3). This publicly available database contains spontaneous reports of adverse drug events and medication errors submitted globally by healthcare professionals and consumers. The database consists of seven standardized datasets: DEMO(demographic information), DRUG(medication details), REAC(reported adverse events), OUCT(outcomes), RPSR(report sources), THER(therapy dates), and INDI(indications) 12 . Reports may involve multiple drugs and ADRs, coded with MedDRA ® PTs, and drugs are assigned roles. As it’s public and anonymized, institutional review board(IRB) approval and consent weren’t needed. FAERS reports for each quarter from 2004Q1 to 2024Q3 were directly downloaded from the FDA, totaling 21,838,627. Potentially related to quarterly updates, duplications existed. Duplicate reports were removed following FDA guidelines 12 : (1) For identical CASEIDs, retain the latest submission based on FDA_DT; (2) When CASEID and FDA_DT matched, select the record with the highest PRIMARYID (indicating most recent submission within the quarter). This reduced reports from 21,838,627 to 18,541,994 (Fig.  1 ). The two-dimensional chemical structure of triptorelin was obtained from PubChem ( https://pubchem.ncbi.nlm.nih.gov/ ) 13 for reference purposes. Triptorelin-associated reports were identified using both brand and generic names(“TRIPTORELIN”, “TRELSTAR”, “DECAPEPTYL”, and “DIPHERELINE”) across the DRUGNAME and PROD_AI fields. The drugs reported in FAERS were categorized into four types: PS (primary suspect), SS (second suspect), C (concomitant), and I (interacting). To improve precision, only the AEs with the role code of PS drug were retained 14 . During the research period, a total of 10,117 AEs reports of triptorelin as the PS drug were identified (FIGURE 1 ). System Organ Class (SOC) is the top level in the Medical Dictionary for Regulatory Activities (MedDRA, version 27.0. Available from https://www.meddra.org/ ) terminology, and all AEs in reports were coded with PTs 15 . Subsequently, 1,462 triptorelin- related PTs were selected. Disproportionality analyses were performed using a case/non-case framework. The case group comprised triptorelin PS reports. The non-case (control) group consisted of all other drug reports in FAERS during the study period – a standard approach for signal screening in spontaneous reporting systems 16 , 17 . A 2 × 2 contingency table (Supplementary Table 1) was constructed for each AE PT/SOC. Time-to-onset (TTO) was calculated as the interval between therapy initiation (START_DT from THER file) and adverse event occurrence (EVENT_DT from DEMO file) 12 , 18 , 19 . To guarantee the precision of the calculation, only reports with complete dates in the YYYYMMDD format were included, and cases with missing/partial dates or logical errors(EVENT_DT before START_DT)were excluded. For a comprehensive evaluation of the TTO, median, quartile, and Weibull shape parameter test were incorporated into our research. The Weibull distribution, with scale (α) and shape (β) as its two parameters for describing the distribution shape, could be used to determine and predict the varying risk of the increase or decrease in the incidence of AEs over time 16 . Subgroup analyses were conducted to investigate the association between triptorelin dosage and adverse effects in subgroups divided according to age ( 64 [elder]) and gender (male and female). Disproportionality analysis is a key tool for detecting potential associations between drugs and adverse events. It is frequently utilized to analyze post-marketing surveillance databases to uncover potential associations for each specific drug-adverse event combination 10 , 20 , 21 . The four algorithms (ROR, PRR, IC, EBGM) were selected because they represent both Frequentist (ROR, PRR) and Bayesian (IC, EBGM) approaches, which are widely validated in pharmacovigilance for balancing sensitivity and specificity in signal detection 17 , 22 – 26 . The IC is used in the BCPNN tool to assess disproportionality. The specific calculation formulas and signal detection thresholds for each method are detailed in Table  1 . The extraction decision rules of these algorithms were applied to detect signals and/or calculate scores for gauging drug-AE associations. An AE signal was identified when at least one of the four indices met the stipulated criteria. Generally, a higher value of the four parameters indicates a stronger signal. A safety signal was defined as meeting the significance criteria in all four algorithms (ROR, PRR, IC, EBGM; see Table  1 ), ensuring robust detection while minimizing false positives 26 , 27 . Novelty/unexpectedness signals refer to any significant AE not listed in the instructions/product label 25 . All data processing and statistical analyses were conducted using Microsoft EXCEL 2023 and R software (R version 4.4.2). Consistent with EMA guidelines 11 , we emphasize that identified signals represent statistical associations requiring further investigation, not established causal relationships.

In summary, this disproportionality analysis of FAERS data identified numerous statistically significant reporting associations between triptorelin and both expected and unexpected AEs, including signals for psychiatric, neurological, growth, and endocrine events. The findings represent potential safety signals requiring hypothesis-testing in robust epidemiological or clinical studies to assess causality. Clinicians should be aware of these associations during risk-benefit assessments, considering factors like timing of onset (noting the bimodal distribution) and potential gender differences (e.g., abdominal pain reports in females). Future research must prioritize overcoming the limitations of spontaneous reporting data to validate and quantify any potential risks suggested here.

Our pharmacovigilance study represents the first comprehensive analysis of triptorelin’s post-marketing safety profile using FAERS data. The identificationof novel signals, including defiant behavior and Alzheimer’s dementia, suggests areas requiring further investigation, though these associations should be interpreted as hypothesis-generating rather than conclusive evidence of causality. Before considering updates to the Summary of Product Characteristics (SmPC), rigorous clinical validation through controlled prospective studies is essential. Notably, several detected adverse events may reflect underlying conditions rather than direct drug effects. The strong statistical signal for Alzheimer’s dementia (ROR = 68.90) was observed predominantly in patients > 64 years, a population with inherent dementia risk. Confounding by age cannot be excluded. For signals like death in prostate cancer patients, disease progression remains the predominant explanation. Disentangling drug effects from underlying malignancy requires studies with matched comparators. The gender distribution of AEs(45.55% females vs. 45.84% males) aligns with triptorelin’s indications for prostate cancer(males) 2 , 4 and endometriosis(females) 1 , 5 , 9 . Additionally, patients under 18 years old accounted for a relatively high proportion (18.22%), consistent with the indication of triptorelin for children 2 years and older with central precocious puberty (CPP) 3 . Notably, we observed an increasing trend in AE since 2019, suggesting both expanded clinical use and heightened pharmacovigilance awareness. While 49.98% of reports came from consumers(often with incomplete data), 47.09% originated from medical professionals (including health professionals, physicians, other health professionals, and pharmacists), providing more reliable safety information. Fig. 3 Age-stratified subgroup analysis of AEs reported with triptorelin. Age-stratified subgroup analysis of AEs reported with triptorelin. Disproportionality analysis identified “reproductive system and breast disorders” and “product issues” as the most prevalent statistically significant signals at the SOC level. Product Issues likely reflect use-related factors (e.g., handling errors or misinterpretation of adverse event descriptions) rather than direct drug effects. Reproductive system and breast disorders signals (e.g., vaginal haemorrhage, breast enlargement, ovarian hyperstimulation syndrome, dysmenorrhoea, testicular atrophy, dyspareunia) align with established triptorelin pharmacology and labeling information. Mechanistically, transient sex steroid hormone surges within 2–4 weeks post-dose may induce puberty-like symptoms (e.g., vaginal bleeding) 28 , 29 , corroborated by clinical observations (incidence: 4.6% in one cohort 29 . Fig. 4 Sex-stratified disproportionality signals of triptorelin-associated AEs. CI , confidence interval; ROR , reporting odds ratio. Sex-stratified disproportionality signals of triptorelin-associated AEs. CI , confidence interval; ROR , reporting odds ratio. Our analysis confirmed triptorelin’s established safety profile through statistically significant signals of expected adverse events (AEs) aligned with its pharmacological mechanism. Vasomotor symptoms dominated the AE spectrum, with hot flushes reported in 71.7% of triptorelin embonate recipients 2 , 4 and 75% in 3-month formulations 1 , consistent with GnRH agonist-induced hypoestrogenism. Other label-congruent signals included sexual dysfunction (testicular atrophy: 7.5% 2 , 4 , reproductive disorders (vaginal haemorrhage, ovarian hyperstimulation syndrome), and metabolic effects (weight increase, hormone abnormalities). These AEs typically manifested within the initial treatment month, were generally self-limiting, and rarely warranted therapy discontinuation 6 – 9 , reinforcing current risk management strategies. Beyond expected effects, disproportionality analysis detected 73 potential safety signals (102 statistically significant PTs), stratified as 36 strong (IC  025 > 3.0) and 23 medium-strength signals (1.5 < IC  025 ≤ 3.0). Crucially, 21 strong signals represented previously unreported associations (Table  2 ). Particularly noteworthy were 21 strong signals representing previously unreported associations that warrant careful evaluation. The detection of Alzheimer-type dementia as a strong signal requires special consideration given the potential confounding by age (21.65% of triptorelin users were > 64 years) and possible misattribution of baseline dementia prevalence in this population. Similarly, signals for psychiatric and behavioral adverse events, including the notably strong signal for defiant behavior in pediatric populations, may reflect either true neuroendocrine effects of GnRH agonists or underlying behavioral conditions in treated populations like central precocious puberty. These novel signals, while requiring validation for causal inference, highlight important potential safety concerns across multiple systems. The neuropsychiatric signals (Alzheimer-type dementia, personality changes), endocrine/growth effects (altered height progression, testosterone decreases), and serious systemic events (pituitary apoplexy, acute coronary syndrome) all merit targeted surveillance and mechanistic investigation. Particularly urgent is the need for rigorous epidemiological studies to evaluate the dementia signal while controlling for age-related confounding, as well as focused research on neuropsychiatric outcomes in pediatric populations receiving GnRH agonists. The biological plausibility of these associations should be explored while considering the limitations inherent in spontaneous reporting data. In Lundstrom’s study, among 120 patients, 115 (95.8%) reported treatment- emergent AEs. 17 patients reported a serious adverse event (SAE), three of whom expired during the study: two succumbed to prostate cancer progression at month 7 and month 8, notwithstanding maintained castration, and a third patient, who was at high risk for coronary occlusion, died of myocardial infarction at month 4. All deaths were adjudged as unrelated to the study drug. Additionally, clinically significant treatment-emergent laboratory abnormalities were observed in nine patients; only two mild events in the same patient were deemed to have a relationship with the study drug. These were increased ALT (to 60 U/L on day 337 [normal range 6–48 U/L]) and AST (to 65 U/L on day 337 [normal range 10–45 U/L]) 2 . In our study, an unexpected mild safety signal, hepatitis fulminant, was also obtained. It is essential to counsel physicians or pharmacists to monitor laboratory abnormalities during triptorelin treatment. The analysis suggests that reports of AEs predominantly occurred within one month. (22.59%) or after one year (25.07%). Consequently, vigilance for these statistically associated AEs may be warranted pending further validation both during the first month and beyond one year. Early detection and management of AEs reported with triptorelin are critical. Notably, comprehensive studies on the precise timing of post-administration adverse reactions are lacking, highlighting the value of our investigation. However, TTO analysis was only feasible for 18% (726/4018) of primary suspect triptorelin reports due to missing or invalid date information. This substantial missing data proportion compromises the generalizability of TTO findings (including median, IQR, and temporal distribution) and introduces potential selection bias. Therefore, these results should be interpreted cautiously, primarily reflecting characteristics of reports with complete temporal data. Triptorelin is a gonadotropin-releasing hormone (GnRH) agonist. Its mechanism of action involves continuous stimulation of pituitary gonadal hormones, leading to receptor down regulation, desensitization of gonadotropin cells, and suppression of gonadotropin (luteinizing hormone, follicle-stimulating hormone), resulting in diminished sex steroid production 28 , 30 . Gender differences in pharmacokinetics may contribute to variations in the reported AE profiles between males and females 31 , 32 . However, there is a paucity of reported gender-specific AEs associated with triptorelin treatment. In our study, we noted that females exhibited a marginally higher number of positive signal values for AEs compared to males. Some of the AEs with strong statistical signals more prone to occur in women included upper abdominal pain, crying, weight increased, hormone level abnormal, increased appetite, epiphyses premature fusion, headache, psychiatric disorders, acne, abnormal hair growth, and abnormal skin odour. Such gender-specific reporting patterns may inform pharmacovigilance monitoring, efficacy, and optimizing drug therapy for both genders. Furthermore, in the age subgroup analysis, some preferred term (PT) specific to each age stage were identified. For instance, vaginal haemorrhage, weight increased, and mood altered signals were present in the subgroup of age < 18; abdominal pain and depression signals were in the subgroup of age 18–64; and hot flush, back pain, increased systolic blood pressure, prostatic specific antigen increased, and muscular weakness signals were in the subgroup of age > 64. Studies have cited that differences in pharmacokinetics with advancing age may either augment or attenuate differences in drug response 33 . The result of age-specific AEs will also assist in augmenting the safety and effectiveness of drugs in specific populations, such as children and the elderly. While our analysis identified significant associations between triptorelin and adverse event reporting in FAERS, several key limitations of spontaneous reporting systems must be emphasized to avoid misinterpretation. Firstly, reporting biases inherent to voluntary systems may distort findings: novel AEs (e.g., defiant behavior) are more likely to be reported due to their unexpectedness, while common labeled events (e.g., hot flashes) may be underreported, potentially skewing signal strength. Additionally, temporal variations in reporting (the Weber effect) and media influence can further complicate signal detection, introducing inconsistencies in how events are captured over time. Secondly, the selection of all non-triptorelin FAERS reports as the comparator group, while consistent with standard disproportionality analysis methodology for initial signal detection 16 , 17 , presents inherent limitations. This approach does not adequately adjust for fundamental differences in patient demographics (e.g., 21.65% elderly users), underlying disease profiles (84.3% malignancy indications), or indication-specific reporting patterns that characterize triptorelin users. To enhance signal specificity in future research, active comparator designs utilizing other GnRH agonists (e.g., leuprolide) would be preferable, as their shared mechanism of action and similar patient populations would better control for confounding by indication. Thirdly, critical methodological constraints persist: the absence of a defined denominator (total number of triptorelin users) precludes calculating incidence rates, limiting our ability to quantify actual risk 34 . Unmeasured confounders—including comorbidities, polypharmacy, and disease severity—further hinder efforts to isolate triptorelin-specific effects, while channeling bias (e.g., preferential use in advanced cancer stages) may introduce additional confounding. Notably, confounding by underlying diseases may distort signals: for example, bone pain in prostate cancer patients could reflect tumor metastasis rather than triptorelin. Concomitant medications (e.g., opioids for cancer pain) might also interact with triptorelin, potentially amplifying musculoskeletal AEs, which we could not disentangle due to data limitations. These limitations underscore that our findings are hypothesis-generating rather than conclusive. Disproportionality analysis effectively identifies statistical signals but cannot establish causality 35 . The results should instead prompt enhanced clinical vigilance and validation through robust epidemiological designs, such as prospective studies, to confirm these associations and clarify their clinical significance.

Triptorelin, a synthetic gonadotropin-releasing hormone(GnRH) analogue first synthesized by Schally in 1973 1 , 2 , is characterized by a D-tryptophan substitution at position 6 (D-Trp 6 -LHRH). This structural modification enhances its receptor binding affinity, resulting in more potent GnRH receptor activation and an extended plasma half-life compared to native GnRH. The pharmacodynamic profile of triptorelin follows a biphasic pattern: initial stimulation of pituitary gonadotropin secretion (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) is followed by sustained receptor downregulation, ultimately leading to suppression of gonadal sex hormone production to castration levels 3 , 4 . Clinically, triptorelin exerts its therapeutic effects through gender-specific endocrine modulation. In males, it suppresses testosterone production for the treatment of hormone-dependent prostate cancer. In females, it inhibits ovarian estrogen synthesis for managing estrogen-dependent conditions such as endometriosis. Additionally, triptorelin is approved for managing central precocious puberty (CPP) in children ≥ 2 years of age by arresting premature activation of the hypothalamic-pituitary-gonadal axis 1 – 3 . The safety profile of triptorelin is primarily driven by its endocrine mechanism of action, inducing testosterone or estrogen suppression (hypogonadism/hypoestrogenism), with adverse reactions (ADRs) documented across clinical trials and post-marketing surveillance. Vasomotor symptoms, particularly hot flashes (> 70%), are the most frequently reported ADR. Gender-specific manifestations include: in male patients, common ADRs (> 10%) encompass sexual dysfunction (impotence, reduced libido), potential acute tumor flare symptoms (e.g., urinary obstruction, bone pain) during initial treatment, and long-term risks of bone loss, osteoporosis, and fractures; in female patients, common ADRs (> 10%) involve gynecological issues (vaginal bleeding, dyspareunia, dysmenorrhea, other vaginal symptoms), reduced libido, headache, sleep disturbances, mood changes, and reports of ovarian hyperstimulation syndrome. Pediatric patients exhibit unique considerations such as vaginal bleeding, nausea/vomiting, allergic reactions, transient growth deceleration, and reversible reduction in trabecular bone mineral density. Notably, the associated trabecular bone loss is generally reversible upon treatment cessation 4 – 9 . The FDA Adverse Event Reporting System (FAERS) serves as a critical pharmacovigilance resource, capturing spontaneously reported adverse drug events for post-marketing safety surveillance 10 . Systematic analysis of FAERS data enables detection of potential safety signals - defined by the European Medicines Agency (EMA) as “information suggesting a new potentially causal association between an intervention and an adverse event that warrants further investigation” 11 . This pharmacovigilance study leverages FAERS data to characterize the real-world safety profile of triptorelin, with particular attention to identifying potential signals that may not have been evident in controlled clinical trials.

Below is the link to the electronic supplementary material. Supplementary Material 1 Supplementary Material 1