A combination of simvastatin and methylprednisolone improves the quality of vitrified-warmed ovarian tissue after auto-transplantation.
OBJECTIVE
Does the preoperative administration of simvastatin and methylprednisolone enhance mouse ovarian quality after auto-transplantation of vitrified-warmed ovarian tissue (OT)?


CONCLUSIONS
Treatment with combined simvastatin and methylprednisolone enhances the quality of transplanted mouse OTs.


BACKGROUND
The prevention of ischemic injury after transplantation of OT is critical for preserving the ovarian follicles. Preoperative administration of simvastatin (a cholesterol-lowering drug) has beneficial effects on various organ transplantations. Moreover, donor treatment with simvastatin and methylprednisolone (main effects are on immune response) prevents ischemia-reperfusion injury and has a beneficial effect on allograft survival in rat cardiac allografts.


METHODS
A total of 232 6-week-old B6D2F1 mice were randomly distributed into fresh control, vitrified-warmed control and experimental groups (n = 10-17 per group). The experimental groups were as follows: sham control, simvastatin, methylprednisolone and co-treatment groups. In the experimental groups, the mice were administered simvastatin (5 mg/kg, orally), methylprednisolone (15 mg/kg, i.v.) or a combination of simvastatin and methylprednisolone 2 h before ovariectomy, whereas the sham control mice received normal saline.


METHODS
Whole ovaries were removed from the mice and vitrified by two-step vitrification procedures. The vitrified ovaries were warmed 1 week later and auto-transplanted under the bilateral kidney capsules. The ovaries and blood samples were collected 2, 7 and 21 days (D) after transplantation for histological analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, immunohistochemistry for CD31 and serum anti-Mullerian hormone (AMH) level estimation. Embryonic development was evaluated after IVF of oocytes obtained from the transplanted ovary.


RESULTS
The group that received simvastatin and methylprednisolone showed a significantly improved intact (Grade 1) follicle ratio (D2: P < 0.001, D7: P < 0.05 and D21: P < 0.001), apoptotic follicle ratio (D21: P < 0.05), CD31-positive area (D7: P < 0.05 and D21: P < 0.05) and serum AMH level (D7: P < 0.001) after transplantation when compared with the sham control. However, no difference was noted in the fertilization and blastocyst formation rates, number of total and apoptotic blastomeres per blastocyst and inner cell mass/trophectoderm ratio among the four transplantation groups.


CONCLUSIONS
Although we evaluated the beneficial effects of simvastatin and methylprednisolone in the present study, we did not unravel the corresponding protective mechanisms.


CONCLUSIONS
Our results suggest that a combination of simvastatin and methylprednisolone has beneficial effects on the quality and functioning of transplanted OT. This combined treatment can potentially be applied clinically to humans and domestic animals subject to further studies.
Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam 463-707, Korea Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul 110-744, Korea.
Jaewang
J
Lee
Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam 463-707, Korea Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul 110-744, Korea.
Eun Jung
EJ
Kim
Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam 463-707, Korea Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul 110-744, Korea.
Hyun Sun
HS
Kong
Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam 463-707, Korea.
Hye Won
HW
Youm
Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam 463-707, Korea Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul 110-744, Korea leejrmd@snu.ac.kr.
Jung Ryeol
JR
Lee
Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam 463-707, Korea Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul 110-744, Korea.
Chang Suk
CS
Suh
Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul 110-744, Korea.
Seok Hyun
SH
Kim
D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015925:Cryopreservation; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology*; D008775:Methylprednisolone / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D010053:Ovary / Q000601:surgery*; D015427:Reperfusion Injury / Q000517:prevention & control*; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology*; D016378:Tissue Transplantation / Q000379:methods*; D014182:Transplantation, Autologous; D058989:Vitrification
D000924:Anticholesteremic Agents; D005938:Glucocorticoids; D019821:Simvastatin; D008775:Methylprednisolone
ischemic injury; methylprednisolone; ovarian tissue; simvastatin; transplantation; vitrification