Long-acting reversible contraception with etonogestrel implants in female macaques (Macaca mulatta and Macaca fascicularis)

INTRODUCTION: Contraception is often required for management and population control purposes in group-housed and free-roaming non-human primates. Long-acting reversible contraceptives, including subdermal progestin-releasing implants, are preferred as they eliminate challenges associated with frequent administration. Etonogestrel (ENG)-releasing subdermal implants are reversible and long-acting for a minimum of 3 years, and are commercially available for human use as Implanon® or Nexplanon®. METHODS: A retrospective analysis was performed detailing the contraceptive effectiveness and reversibility of subdermal placement of one-fourth or one-third of an ENG implant (68 mg/implant) in 129 female rhesus macaques (Macaca mulatta) and 67 cynomolgus macaques (Macaca fascicularis) at the Biomedical Primate Research Centre (Rijswijk, Netherlands). Furthermore, single cross-sectional ENG serum concentrations were measured for 16 rhesus and 10 cynomolgus macaques, and hemoglobin and blood chemistry pre-ENG and at timepoints >0.5, >1.5, and > 2.5 years post-ENG insertion were evaluated for 24 rhesus macaques. Finally, data were obtained using trans-abdominal ultrasound regarding the influence of ENG on uterine volume and endometrial thickness in 14 rhesus and 11 cynomolgus macaques. RESULTS: As a contraceptive ENG was in 99.80% (CI 93.50-99.99) and 99.95% (CI 99.95-100) effective in rhesus and cynomolgus macaques, respectively. Prolonged ENG durations of implant use in 14 rhesus macaques (range 3.1-5.0 years) and eight cynomolgus macaques (range 3.2-4.0 years) resulted in no unintended pregnancies. A total of 17 female macaques were allowed to breed after ENG removal, and among them, 14 female macaques (82%) had an uneventful delivery. Serum ENG concentrations with a median ENG duration of 1.2 years (range 0.1-6.0 years) and 1.9 years (range 0.6-4.7 years) resulted in median concentrations of 112 pg./mL (range 0-305 pg./mL) and 310 pg./mL (range 183-382 pg./mL) for rhesus and cynomolgus macaques, respectively. ENG had no clinical effect on hemoglobin and blood chemistry parameters nor on the thickness of the endometrial lining or uterus volume. CONCLUSION: This study indicates that both one-fourth and one-third of the ENG implants are effective, long-acting, reversible, and safe contraceptive to use in macaques

Retrospective Analysis of the Effectiveness and Reversibility of Long-Acting Contraception Etonogestrel (Implanon®) in Common Marmosets (Callithrix jacchus)

Contraception is an important population control method for the colony management of primates housed in captivity. Etonogestrel (ENG) implants (i.e., Implanon®) are a widely used progestin-based contraceptive in common marmosets (Callithrix jacchus) with the theoretical advantages of being reversible and long-acting. However, no dose and efficacy data are available yet. Therefore, data from 52 adult female marmosets contracepted with ENG (one-fourth or one-third of an implant) housed at the Biomedical Primate Research Centre (BPRC, Rijswijk, The Netherlands) over the past 18 years were analyzed. Using an electronic database, a retrospective longitudinal cohort study was conducted to calculate the reproductive data before, during and after ENG use. The data show an effectiveness in preventing pregnancy of 99%. The implant was effective within one week after insertion. Unintended pregnancies did occur, but in 60% of these cases, the animals were already pregnant at the time of implant insertion. In these cases, healthy offspring were born despite the use of the implant. No stillbirths, neonatal deaths or maternal deaths could be linked to ENG use. After implant removal, 83% of the animals delivered healthy offspring. No difference in contraception efficacy was observed between the use of one-fourth or one-third of an implant. ENG achieved a contraceptive protection exceeding 99% and was shown to be reversible concerning fertility. To our knowledge, this is the first detailed analysis on the use of ENG in marmosets

Effects of buprenorphine, butorphanol or tramadol premedication on anaesthetic induction with alfaxalone in common marmosets (Callithrix jacchus)

OBJECTIVE: To investigate the clinical and physiological effects of intravenous (IV) alfaxalone alone or in combination with buprenorphine, butorphanol or tramadol premedication in marmosets. STUDY DESIGN: Prospective, randomized, blinded, crossover design. ANIMALS: Nine healthy marmosets (391 ± 48 g, 3.7 ± 2.2 years old). METHODS: Meloxicam 0.20 mg kg-1 subcutaneously, atropine 0.05 mg kg-1 intramuscularly (IM) and either buprenorphine 20 μg kg-1 IM (BUP-A), butorphanol 0.2 mg kg-1 IM (BUT-A), tramadol 1.5 mg kg-1 IM (TRA-A) or no additional drug (control) were administered to all marmosets as premedication. After 1 hour, anaesthesia was induced with 16 mg kg-1 alfaxalone IV. All animals received all protocols. The order of protocol allocation was randomized with a minimum 28 day wash-out period. During anaesthesia, respiratory and pulse rates, rectal temperature, haemoglobin oxygen saturation, arterial blood pressure, palpebral and pedal withdrawal reflexes and degree of muscle relaxation were assessed and recorded every 5 minutes. Quality of induction and recovery were assessed. Duration of induction, immobilization and recovery were recorded. Blood samples were analysed for aspartate aminotransferase, creatine kinase and lactate dehydrogenase concentrations. The protocols were compared using paired t tests, Wilcoxon's signed-rank test with Bonferroni's corrections and linear mixed effect models where appropriate. RESULTS: Out of nine animals, apnoea was noted in eight animals administered protocol BUP-A and two animals administered protocol BUT-A. With TRA-A and control protocols, apnoea was not observed. No other significant differences in any of the parameters were found; however, low arterial blood pressures and hypoxia occurred in TRA-A. CONCLUSIONS AND CLINICAL RELEVANCE: Our study employing different premedications suggests that the previously published dose of 16 mg kg-1 alfaxalone is too high when used with premedication because we found a high incidence of complications including apnoea (BUP-A), hypotension and hypoxaemia (TRA-A). Appropriate monitoring and countermeasures are recommended

Effects of buprenorphine, butorphanol or tramadol premedication on anaesthetic induction with alfaxalone in common marmosets (Callithrix jacchus)

OBJECTIVE: To investigate the clinical and physiological effects of intravenous (IV) alfaxalone alone or in combination with buprenorphine, butorphanol or tramadol premedication in marmosets. STUDY DESIGN: Prospective, randomized, blinded, crossover design. ANIMALS: Nine healthy marmosets (391 ± 48 g, 3.7 ± 2.2 years old). METHODS: Meloxicam 0.20 mg kg-1 subcutaneously, atropine 0.05 mg kg-1 intramuscularly (IM) and either buprenorphine 20 μg kg-1 IM (BUP-A), butorphanol 0.2 mg kg-1 IM (BUT-A), tramadol 1.5 mg kg-1 IM (TRA-A) or no additional drug (control) were administered to all marmosets as premedication. After 1 hour, anaesthesia was induced with 16 mg kg-1 alfaxalone IV. All animals received all protocols. The order of protocol allocation was randomized with a minimum 28 day wash-out period. During anaesthesia, respiratory and pulse rates, rectal temperature, haemoglobin oxygen saturation, arterial blood pressure, palpebral and pedal withdrawal reflexes and degree of muscle relaxation were assessed and recorded every 5 minutes. Quality of induction and recovery were assessed. Duration of induction, immobilization and recovery were recorded. Blood samples were analysed for aspartate aminotransferase, creatine kinase and lactate dehydrogenase concentrations. The protocols were compared using paired t tests, Wilcoxon's signed-rank test with Bonferroni's corrections and linear mixed effect models where appropriate. RESULTS: Out of nine animals, apnoea was noted in eight animals administered protocol BUP-A and two animals administered protocol BUT-A. With TRA-A and control protocols, apnoea was not observed. No other significant differences in any of the parameters were found; however, low arterial blood pressures and hypoxia occurred in TRA-A. CONCLUSIONS AND CLINICAL RELEVANCE: Our study employing different premedications suggests that the previously published dose of 16 mg kg-1 alfaxalone is too high when used with premedication because we found a high incidence of complications including apnoea (BUP-A), hypotension and hypoxaemia (TRA-A). Appropriate monitoring and countermeasures are recommended

Retrospective Analysis of the Effectiveness and Reversibility of Long-Acting Contraception Etonogestrel (Implanon®) in Common Marmosets (Callithrix jacchus)

Contraception is an important population control method for the colony management of primates housed in captivity. Etonogestrel (ENG) implants (i.e., Implanon®) are a widely used pro-gestin-based contraceptive in common marmosets (Callithrix jacchus) with the theoretical advantages of being reversible and long-acting. However, no dose and efficacy data are available yet. Therefore, data from 52 adult female marmosets contracepted with ENG (one-fourth or one-third of an implant) housed at the Biomedical Primate Research Centre (BPRC, Rijswijk, The Netherlands) over the past 18 years were analyzed. Using an electronic database, a retrospective longitudinal cohort study was conducted to calculate the reproductive data before, during and after ENG use. The data show an effectiveness in preventing pregnancy of 99%. The implant was effective within one week after insertion. Unintended pregnancies did occur, but in 60% of these cases, the animals were already pregnant at the time of implant insertion. In these cases, healthy offspring were born despite the use of the implant. No stillbirths, neonatal deaths or maternal deaths could be linked to ENG use. After implant removal, 83% of the animals delivered healthy offspring. No difference in contraception efficacy was observed between the use of one-fourth or one-third of an implant. ENG achieved a contraceptive protection exceeding 99% and was shown to be reversible concerning fer-tility. To our knowledge, this is the first detailed analysis on the use of ENG in marmosets

Retrospective Analysis of the Effectiveness and Reversibility of Long-Acting Contraception Etonogestrel (Implanon®) in Common Marmosets (Callithrix jacchus)

Contraception is an important population control method for the colony management of primates housed in captivity. Etonogestrel (ENG) implants (i.e., Implanon®) are a widely used pro-gestin-based contraceptive in common marmosets (Callithrix jacchus) with the theoretical advantages of being reversible and long-acting. However, no dose and efficacy data are available yet. Therefore, data from 52 adult female marmosets contracepted with ENG (one-fourth or one-third of an implant) housed at the Biomedical Primate Research Centre (BPRC, Rijswijk, The Netherlands) over the past 18 years were analyzed. Using an electronic database, a retrospective longitudinal cohort study was conducted to calculate the reproductive data before, during and after ENG use. The data show an effectiveness in preventing pregnancy of 99%. The implant was effective within one week after insertion. Unintended pregnancies did occur, but in 60% of these cases, the animals were already pregnant at the time of implant insertion. In these cases, healthy offspring were born despite the use of the implant. No stillbirths, neonatal deaths or maternal deaths could be linked to ENG use. After implant removal, 83% of the animals delivered healthy offspring. No difference in contraception efficacy was observed between the use of one-fourth or one-third of an implant. ENG achieved a contraceptive protection exceeding 99% and was shown to be reversible concerning fer-tility. To our knowledge, this is the first detailed analysis on the use of ENG in marmosets

Data_Sheet_1_Long-acting reversible contraception with etonogestrel implants in female macaques (Macaca mulatta and Macaca fascicularis).docx

IntroductionContraception is often required for management and population control purposes in group-housed and free-roaming non-human primates. Long-acting reversible contraceptives, including subdermal progestin-releasing implants, are preferred as they eliminate challenges associated with frequent administration. Etonogestrel (ENG)-releasing subdermal implants are reversible and long-acting for a minimum of 3 years, and are commercially available for human use as Implanon® or Nexplanon®.MethodsA retrospective analysis was performed detailing the contraceptive effectiveness and reversibility of subdermal placement of one-fourth or one-third of an ENG implant (68 mg/implant) in 129 female rhesus macaques (Macaca mulatta) and 67 cynomolgus macaques (Macaca fascicularis) at the Biomedical Primate Research Centre (Rijswijk, Netherlands). Furthermore, single cross-sectional ENG serum concentrations were measured for 16 rhesus and 10 cynomolgus macaques, and hemoglobin and blood chemistry pre-ENG and at timepoints >0.5, >1.5, and > 2.5 years post-ENG insertion were evaluated for 24 rhesus macaques. Finally, data were obtained using trans-abdominal ultrasound regarding the influence of ENG on uterine volume and endometrial thickness in 14 rhesus and 11 cynomolgus macaques.ResultsAs a contraceptive ENG was in 99.80% (CI 93.50–99.99) and 99.95% (CI 99.95–100) effective in rhesus and cynomolgus macaques, respectively. Prolonged ENG durations of implant use in 14 rhesus macaques (range 3.1–5.0 years) and eight cynomolgus macaques (range 3.2–4.0 years) resulted in no unintended pregnancies. A total of 17 female macaques were allowed to breed after ENG removal, and among them, 14 female macaques (82%) had an uneventful delivery. Serum ENG concentrations with a median ENG duration of 1.2 years (range 0.1–6.0 years) and 1.9 years (range 0.6–4.7 years) resulted in median concentrations of 112 pg./mL (range 0–305 pg./mL) and 310 pg./mL (range 183–382 pg./mL) for rhesus and cynomolgus macaques, respectively. ENG had no clinical effect on hemoglobin and blood chemistry parameters nor on the thickness of the endometrial lining or uterus volume.ConclusionThis study indicates that both one-fourth and one-third of the ENG implants are effective, long-acting, reversible, and safe contraceptive to use in macaques.</p