Uterus allotransplantation in cynomolgus macaque: A preliminary experience with non‐human primate models

Abstract

Aim: Uterine transplantation (UTx) is a potential option for child-bearing in women with uterine infertility. Recovery of uterine function after allogeneic UTx in non-human primates has not been reported. The objective of this study is to establish the functional uterine transplant model in non-human primates. Methods: Uteri of two cynomolgus monkeys were simultaneously removed, cooled at 4°C and perfused with heparin saline. The uteri were interchanged with each other and then orthotopically transplanted. Immunosuppressive protocols included use of three agents (tacrolimus, mycophenolate mofetil and methylprednisolone) in case 1 and two agents (tacrolimus and methylprednisolone) in case 2. Transabdominal ultrasonography, vaginoscopy and biopsy of the transplanted uterine cervix were routinely conducted to monitor rejection after surgery. Results: The blood concentration of tacrolimus decreased 11 days after surgery and evidence of rejection was found in biopsy of the uterine cervix in both cases. The suspected rejection disappeared 23 days after surgery in case 1 and temporary menstruation resumed at 3 months after surgery. In case 2, blood flow to the uterine artery gradually decreased and the uterus resulted in atrophy due to ischemia, which has been triggered by rejection. Conclusion: Allogeneic UTx in the cynomolgus monkeys resulted in temporary recovery of menstruation with three immunosuppressants and uterine atrophy with two immunosuppressants. This preliminary experience suggests that recovery of uterine function after allogeneic UTx in non-human primates is possible but more experiments are required.

Cynomolgus monkeys are successfully and persistently infected with hepatitis E virus genotype 3 (HEV-3) after long-term immunosuppressive therapy

“…The rate of absorption and the bioavailability of tacrolimus after oral administration (which was the chosen administration via, in our study) appear to be variable in all the patient populations studied [51]. It was extremely difficult to control the blood concentrations of oral tacrolimus in our cynomolgus monkeys, as also reported by other authors [52], therefore the dose had to be adjusted throughout the experiment. At 149 dpi, tacrolimus dose was reduced from 3.5 mg/kg/day to 2.0 mg/kg/day, since some animals exhibited herpetic lesions assumed as opportunistic infection.…”

Recent advances in the molecular mechanisms of Mayer-Rokitansky-Küster-Hauser syndrome

“…Thus, patients with MRKHS have successfully undergone uterine transplantation (34). In Japan, uterine transplantation has been examined in cynomolgus monkeys (35,36). The uterus was exchanged between two cynomolgus monkeys and one successfully achieved natural pregnancy following menstruation (36).…”

The history behind successful uterine transplantation in humans

“…A direct offspring was achieved. In a follow-up study on allogeneic UTx in this species, resumption of menstruation was seen in an animal under immunosuppression with tacrolimus, methylprednisolone, and mycophenolate mofetil (Kisu et al , 2014). …”