Free Standard AU & NZ Shipping For All Book Orders Over $80!
Register      Login
Reproduction, Fertility and Development Reproduction, Fertility and Development Society
Vertebrate reproductive science and technology
RESEARCH ARTICLE

l-Carnitine improves follicular survival and function in ovarian grafts in the mouse

Khadijeh Sanamiri https://orcid.org/0000-0001-6848-2729 A , Malek Soleimani Mehranjani https://orcid.org/0000-0003-0899-003X A * , Maryam Shahhoseini https://orcid.org/0000-0002-9021-6408 B and Mohammad Ali Shariatzadeh https://orcid.org/0000-0002-2395-8057 A
+ Author Affiliations
- Author Affiliations

A Department of Biology, Faculty of Science, Arak University, Arak, Iran.

B Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.

* Correspondence to: m-Soleimani@araku.ac.ir

Handling Editor: Geraldine Hartshorne

Reproduction, Fertility and Development 34(10) 713-721 https://doi.org/10.1071/RD21287
Published online: 3 May 2022

© 2022 The Author(s) (or their employer(s)). Published by CSIRO Publishing

Abstract

Context: Ovarian tissue transplantation is performed to preserve fertility in patients undergoing chemotherapy and radiotherapy. However, the ischemia-reperfusion injury which occurs after the ovarian tissue transplantation causes follicular depletion and apoptosis. l-Carnitine has antioxidant and anti-inflammation properties.

Aims: Therefore, we aimed to investigate the beneficial effect of l-carnitine on mouse ovaries following heterotopic autotransplantation.

Methods: Mice were randomly divided into three groups (six mice per group): control, autografted and autografted + l-carnitine (200 mg/kg daily intraperitoneal injections). Seven days after ovary autografting, the serum levels of malondialdehyde (MDA), total antioxidant capacity, tumor necrosis factor alpha (TNF-α), interleukin (IL)-6 and IL-10 were measured. Ovary histology, serum concentrations of progesterone and estradiol were also measured 28 days after autotransplantation. Data were analysed using one-way analysis of variance (ANOVA) and Tukey test, and the means were considered significantly different at P < 0.05.

Key results: In the autografted + l-carnitine group, the total volume of the ovary, the volume of the cortex, the number of follicles, the serum concentrations of IL-10, estradiol and progesterone significantly increased compared to the autografted group. In the autografted + l-carnitine group, serum concentrations of IL-6, TNF-α and MDA were significantly decreased compared to the autografted group.

Conclusions: Our results indicated that l-carnitine can ameliorate the consequences of ischemia-reperfusion on the mice ovarian tissue following autotransplantation.

Implications: l-carnitine improves the structure and function of transplanted ovaries.

Keywords: folliculogenesis, inflammation, ischemia–reperfusion, L-carnitine, mouse, ovary transplantation, oxidative stress, stereology.


References

Baird, DT, Webb, R, Campbell, BK, et al. (1999). Long-term ovarian function in sheep after ovariectomy and transplantation of autografts stored at −196 C. Endocrinology 140, 462–471.
Long-term ovarian function in sheep after ovariectomy and transplantation of autografts stored at −196 C.Crossref | GoogleScholarGoogle Scholar | 9886858PubMed |

Bavari, M, Tabandeh, MR, Najafzadeh Varzi, H, et al. (2016). Neuroprotective, antiapoptotic and antioxidant effects of l-carnitine against caffeine-induced neurotoxicity in SH-SY5Y neuroblastoma cell line. Drug and Chemical Toxicology 39, 157–166.
Neuroprotective, antiapoptotic and antioxidant effects of l-carnitine against caffeine-induced neurotoxicity in SH-SY5Y neuroblastoma cell line.Crossref | GoogleScholarGoogle Scholar | 26136110PubMed |

Benzie, IFF, and Strain, JJ (1996). The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay. Analytical Biochemistry 239, 70–76.
The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay.Crossref | GoogleScholarGoogle Scholar |

Buege JA, Aust SD (1978) [30] Microsomal lipid peroxidation. In ‘Methods in enzymology. Vol. 52’. (Eds S Fleischer, L Packer) pp. 302–310. (Academic Press)
| Crossref |

Çekin, AH, Gür, G, Türkoğlu, S, et al. (2013). The protective effect of l-carnitine on hepatic ischemia-reperfusion injury in rats. Turkish Journal of Gastroenterology 24, 51–56.
The protective effect of l-carnitine on hepatic ischemia-reperfusion injury in rats.Crossref | GoogleScholarGoogle Scholar |

Celik, S, Ozkavukcu, S, and Celik-Ozenci, C (2020). Altered expression of activator proteins that control follicle reserve after ovarian tissue cryopreservation/transplantation and primordial follicle loss prevention by rapamycin. Journal of Assisted Reproduction and Genetics 37, 2119–2136.
Altered expression of activator proteins that control follicle reserve after ovarian tissue cryopreservation/transplantation and primordial follicle loss prevention by rapamycin.Crossref | GoogleScholarGoogle Scholar | 32651677PubMed |

Commin, L, Buff, S, Rosset, E, et al. (2012). Follicle development in cryopreserved bitch ovarian tissue grafted to immunodeficient mouse. Reproduction, Fertility and Development 24, 461–471.
Follicle development in cryopreserved bitch ovarian tissue grafted to immunodeficient mouse.Crossref | GoogleScholarGoogle Scholar |

Damous, LL, Silva, SM, Carbonel, APF, et al. (2009). Effect of remote ischemic preconditioning on rat estradiol serum levels and follicular development after ovarian transplantation. Transplantation Proceedings 41, 830–833.
Effect of remote ischemic preconditioning on rat estradiol serum levels and follicular development after ovarian transplantation.Crossref | GoogleScholarGoogle Scholar | 19376364PubMed |

Demeestere, I, Simon, P, Emiliani, S, et al. (2009). Orthotopic and heterotopic ovarian tissue transplantation. Human Reproduction Update 15, 649–665.
Orthotopic and heterotopic ovarian tissue transplantation.Crossref | GoogleScholarGoogle Scholar | 19474206PubMed |

Dolmans, M-M, and Manavella, DD (2019). Recent advances in fertility preservation. Journal of Obstetrics and Gynaecology Research 45, 266–279.
Recent advances in fertility preservation.Crossref | GoogleScholarGoogle Scholar |

Dolmans, M-M, Cacciottola, L, Amorim, CA, et al. (2019). Translational research aiming to improve survival of ovarian tissue transplants using adipose tissue-derived stem cells. Acta Obstetricia et Gynecologica Scandinavica 98, 665–671.
Translational research aiming to improve survival of ovarian tissue transplants using adipose tissue-derived stem cells.Crossref | GoogleScholarGoogle Scholar | 30891730PubMed |

Dunning, KR, Cashman, K, Russell, DL, et al. (2010). Beta-oxidation is essential for mouse oocyte developmental competence and early embryo development. Biology of Reproduction 83, 909–918.
Beta-oxidation is essential for mouse oocyte developmental competence and early embryo development.Crossref | GoogleScholarGoogle Scholar | 20686180PubMed |

Dunning, KR, Akison, LK, Russell, DL, et al. (2011). Increased beta-oxidation and improved oocyte developmental competence in response to l-Carnitine during ovarian in vitro follicle development in mice. Biology of Reproduction 85, 548–555.
Increased beta-oxidation and improved oocyte developmental competence in response to l-Carnitine during ovarian in vitro follicle development in mice.Crossref | GoogleScholarGoogle Scholar | 21613630PubMed |

Eimani, H, Siadat, SF, Eftekhari-Yazdi, P, et al. (2009). Comparative study between intact and non-intact intramuscular auto-grafted mouse ovaries. Reproductive BioMedicine Online 18, 53–60.
Comparative study between intact and non-intact intramuscular auto-grafted mouse ovaries.Crossref | GoogleScholarGoogle Scholar | 19146769PubMed |

Ferreira, GC, and McKenna, MC (2017). l-Carnitine and acetyl-l-carnitine roles and neuroprotection in developing brain. Neurochemical Research 42, 1661–1675.
l-Carnitine and acetyl-l-carnitine roles and neuroprotection in developing brain.Crossref | GoogleScholarGoogle Scholar | 28508995PubMed |

Giudetti, AM, Stanca, E, Siculella, L, et al. (2016). Nutritional and hormonal regulation of citrate and carnitine/acylcarnitine transporters: two mitochondrial carriers involved in fatty acid metabolism. International Journal of Molecular Sciences 17, 817.
Nutritional and hormonal regulation of citrate and carnitine/acylcarnitine transporters: two mitochondrial carriers involved in fatty acid metabolism.Crossref | GoogleScholarGoogle Scholar |

Greenfeld, CR, Babus, JK, Furth, PA, et al. (2007). BAX is involved in regulating follicular growth, but is dispensable for follicle atresia in adult mouse ovaries. Reproduction 133, 107–116.
BAX is involved in regulating follicular growth, but is dispensable for follicle atresia in adult mouse ovaries.Crossref | GoogleScholarGoogle Scholar | 17244737PubMed |

Gülçin, İ (2006). Antioxidant and antiradical activities of l-carnitine. Life Sciences 78, 803–811.
Antioxidant and antiradical activities of l-carnitine.Crossref | GoogleScholarGoogle Scholar | 16253281PubMed |

Hemadi, M, Abolhassani, F, Akbari, M, et al. (2009). Melatonin promotes the cumulus–oocyte complexes quality of vitrified–thawed murine ovaries; with increased mean number of follicles survival and ovary size following heterotopic transplantation. European Journal of Pharmacology 618, 84–90.
Melatonin promotes the cumulus–oocyte complexes quality of vitrified–thawed murine ovaries; with increased mean number of follicles survival and ovary size following heterotopic transplantation.Crossref | GoogleScholarGoogle Scholar | 19622351PubMed |

Hoekman, EJ, Louwe, LA, Rooijers, M, et al. (2020). Ovarian tissue cryopreservation: low usage rates and high live-birth rate after transplantation. Acta Obstetricia et Gynecologica Scandinavica 99, 213–221.
Ovarian tissue cryopreservation: low usage rates and high live-birth rate after transplantation.Crossref | GoogleScholarGoogle Scholar | 31538662PubMed |

Jiang, F, Zhang, Z, Zhang, Y, et al. (2016). l-carnitine ameliorates the liver inflammatory response by regulating carnitine palmitoyltransferase I-dependent PPARγ signaling. Molecular Medicine Reports 13, 1320–1328.
l-carnitine ameliorates the liver inflammatory response by regulating carnitine palmitoyltransferase I-dependent PPARγ signaling.Crossref | GoogleScholarGoogle Scholar | 26647854PubMed |

Kalhori, Z, Soleimani Mehranjani, M, Azadbakht, M, et al. (2019). l-Carnitine improves endocrine function and folliculogenesis by reducing inflammation, oxidative stress and apoptosis in mice following induction of polycystic ovary syndrome. Reproduction, Fertility and Development 31, 282–293.
l-Carnitine improves endocrine function and folliculogenesis by reducing inflammation, oxidative stress and apoptosis in mice following induction of polycystic ovary syndrome.Crossref | GoogleScholarGoogle Scholar |

Karbalay-Doust, S, and Noorafshan, A (2012). Stereological estimation of ovarian oocyte volume, surface area and number: application on mice treated with nandrolone decanoate. Folia Histochemica et Cytobiologica 50, 275–279.
Stereological estimation of ovarian oocyte volume, surface area and number: application on mice treated with nandrolone decanoate.Crossref | GoogleScholarGoogle Scholar | 22763965PubMed |

Kim, MK, Park, JK, Paek, SK, et al. (2018). Effects and pregnancy outcomes of l-carnitine supplementation in culture media for human embryo development from in vitro fertilization. Journal of Obstetrics and Gynaecology Research 44, 2059–2066.
Effects and pregnancy outcomes of l-carnitine supplementation in culture media for human embryo development from in vitro fertilization.Crossref | GoogleScholarGoogle Scholar |

Kitano, Y, Hashimoto, S, Matsumoto, H, et al. (2018). Oral administration of l-carnitine improves the clinical outcome of fertility in patients with IVF treatment. Gynecological Endocrinology 34, 684–688.
Oral administration of l-carnitine improves the clinical outcome of fertility in patients with IVF treatment.Crossref | GoogleScholarGoogle Scholar | 29378447PubMed |

Koc, A, Ozkan, T, Karabay, AZ, et al. (2011). Effect of l-carnitine on the synthesis of nitric oxide in RAW 264·7 murine macrophage cell line. Cell Biochemistry & Function 29, 679–685.
Effect of l-carnitine on the synthesis of nitric oxide in RAW 264·7 murine macrophage cell line.Crossref | GoogleScholarGoogle Scholar |

Liu, J, Van der Elst, J, Van den Broecke, R, et al. (2002). Early massive follicle loss and apoptosis in heterotopically grafted newborn mouse ovaries. Human Reproduction 17, 605–611.
Early massive follicle loss and apoptosis in heterotopically grafted newborn mouse ovaries.Crossref | GoogleScholarGoogle Scholar | 11870111PubMed |

Mahmoodi, M, Soleimani Mehranjani, M, Shariatzadeh, SMA, et al. (2014). Effects of erythropoietin on ischemia, follicular survival, and ovarian function in ovarian grafts. Reproduction 147, 733–741.
Effects of erythropoietin on ischemia, follicular survival, and ovarian function in ovarian grafts.Crossref | GoogleScholarGoogle Scholar | 24492857PubMed |

Mahmoodi, M, Soleimani Mehranjani, M, Shariatzadeh, SMA, et al. (2015). N-acetylcysteine improves function and follicular survival in mice ovarian grafts through inhibition of oxidative stress. Reproductive BioMedicine Online 30, 101–110.
N-acetylcysteine improves function and follicular survival in mice ovarian grafts through inhibition of oxidative stress.Crossref | GoogleScholarGoogle Scholar | 25458850PubMed |

Manavella, DD, Cacciottola, L, Desmet, CM, et al. (2018). Adipose tissue-derived stem cells in a fibrin implant enhance neovascularization in a peritoneal grafting site: a potential way to improve ovarian tissue transplantation. Human Reproduction 33, 270–279.
Adipose tissue-derived stem cells in a fibrin implant enhance neovascularization in a peritoneal grafting site: a potential way to improve ovarian tissue transplantation.Crossref | GoogleScholarGoogle Scholar | 29304240PubMed |

Moawad, AR, Tan, SL, Xu, B, et al. (2013). l-carnitine supplementation during vitrification of mouse oocytes at the germinal vesicle stage improves preimplantation development following maturation and fertilization in vitro. Biology of Reproduction 88, 1–8.
l-carnitine supplementation during vitrification of mouse oocytes at the germinal vesicle stage improves preimplantation development following maturation and fertilization in vitro.Crossref | GoogleScholarGoogle Scholar |

Moawad, AR, Xu, B, Tan, SL, et al. (2014). l-carnitine supplementation during vitrification of mouse germinal vesicle stage-oocytes and their subsequent in vitro maturation improves meiotic spindle configuration and mitochondrial distribution in metaphase II oocytes. Human Reproduction 29, 2256–2268.
l-carnitine supplementation during vitrification of mouse germinal vesicle stage-oocytes and their subsequent in vitro maturation improves meiotic spindle configuration and mitochondrial distribution in metaphase II oocytes.Crossref | GoogleScholarGoogle Scholar | 25113843PubMed |

Moghaddas, A, and Dashti-Khavidaki, S (2016). Potential protective effects of l-carnitine against neuromuscular ischemia-reperfusion injury: from experimental data to potential clinical applications. Clinical Nutrition 35, 783–790.
Potential protective effects of l-carnitine against neuromuscular ischemia-reperfusion injury: from experimental data to potential clinical applications.Crossref | GoogleScholarGoogle Scholar | 26199084PubMed |

Moghaddas, A, and Dashti-Khavidaki, S (2018). l-Carnitine and potential protective effects against ischemia-reperfusion injury in noncardiac organs: from experimental data to potential clinical applications. Journal of Dietary Supplements 15, 740–756.
l-Carnitine and potential protective effects against ischemia-reperfusion injury in noncardiac organs: from experimental data to potential clinical applications.Crossref | GoogleScholarGoogle Scholar | 29053424PubMed |

Myers, M, Britt, KL, Wreford, NGM, et al. (2004). Methods for quantifying follicular numbers within the mouse ovary. Reproduction 127, 569–580.
Methods for quantifying follicular numbers within the mouse ovary.Crossref | GoogleScholarGoogle Scholar | 15129012PubMed |

Noori Hassanvand, M, Soleimani Mehranjani, M, and Shojafar, E (2019). Melatonin improves the structure and function of autografted mice ovaries through reducing inflammation: a stereological and biochemical analysis. International Immunopharmacology 74, 105679.
Melatonin improves the structure and function of autografted mice ovaries through reducing inflammation: a stereological and biochemical analysis.Crossref | GoogleScholarGoogle Scholar | 31202180PubMed |

Oktay, KH, Marin, L, Petrikovsky, B, et al. (2021). Delaying reproductive aging by ovarian tissue cryopreservation and transplantation: is it prime time? Trends in Molecular Medicine 27, 753–761.
Delaying reproductive aging by ovarian tissue cryopreservation and transplantation: is it prime time?Crossref | GoogleScholarGoogle Scholar | 33549473PubMed |

Setia, S, and Sanyal, SN (2012). Downregulation of NF-κB and PCNA in the regulatory pathways of apoptosis by cyclooxygenase-2 inhibitors in experimental lung cancer. Molecular and Cellular Biochemistry 369, 75–86.
Downregulation of NF-κB and PCNA in the regulatory pathways of apoptosis by cyclooxygenase-2 inhibitors in experimental lung cancer.Crossref | GoogleScholarGoogle Scholar | 22752388PubMed |

Shojafar, E, Soleimani Mehranjani, M, and Shariatzadeh, SMA (2018). Adipose-derived mesenchymal stromal cell transplantation at the graft site improves the structure and function of autografted mice ovaries: a stereological and biochemical analysis. Cytotherapy 20, 1324–1336.
Adipose-derived mesenchymal stromal cell transplantation at the graft site improves the structure and function of autografted mice ovaries: a stereological and biochemical analysis.Crossref | GoogleScholarGoogle Scholar | 30360962PubMed |

Shojafar, E, Soleimani Mehranjani, M, and Shariatzadeh, SMA (2019). Adipose derived mesenchymal stem cells improve the structure and function of autografted mice ovaries through reducing oxidative stress and inflammation: a stereological and biochemical analysis. Tissue and Cell 56, 23–30.
Adipose derived mesenchymal stem cells improve the structure and function of autografted mice ovaries through reducing oxidative stress and inflammation: a stereological and biochemical analysis.Crossref | GoogleScholarGoogle Scholar | 30736901PubMed |

Siomek, A (2012). NF-κB signaling pathway and free radical impact. Acta Biochimica Polonica 59, 323–331.
NF-κB signaling pathway and free radical impact.Crossref | GoogleScholarGoogle Scholar | 22855720PubMed |

Slegtenhorst, BR, Dor, FJMF, Rodriguez, H, et al. (2014). Ischemia/reperfusion injury and its consequences on immunity and inflammation. Current Transplantation Reports 1, 147–154.
Ischemia/reperfusion injury and its consequences on immunity and inflammation.Crossref | GoogleScholarGoogle Scholar | 25419507PubMed |

Steiber, A, Kerner, J, and Hoppel, CL (2004). Carnitine: a nutritional, biosynthetic, and functional perspective. Molecular Aspects of Medicine 25, 455–473.
Carnitine: a nutritional, biosynthetic, and functional perspective.Crossref | GoogleScholarGoogle Scholar | 15363636PubMed |

Takae, S, and Suzuki, N (2019). Current state and future possibilities of ovarian tissue transplantation. Reproductive Medicine and Biology 18, 217–224.
Current state and future possibilities of ovarian tissue transplantation.Crossref | GoogleScholarGoogle Scholar | 31312099PubMed |

Van Eyck, A-S, Jordan, BF, Gallez, B, et al. (2009). Electron paramagnetic resonance as a tool to evaluate human ovarian tissue reoxygenation after xenografting. Fertility and Sterility 92, 374–381.
Electron paramagnetic resonance as a tool to evaluate human ovarian tissue reoxygenation after xenografting.Crossref | GoogleScholarGoogle Scholar | 18692811PubMed |

Wang, L, Ying, Y-f, Ouyang, Y-l, et al. (2013). VEGF and bFGF increase survival of xenografted human ovarian tissue in an experimental rabbit model. Journal of Assisted Reproduction and Genetics 30, 1301–1311.
VEGF and bFGF increase survival of xenografted human ovarian tissue in an experimental rabbit model.Crossref | GoogleScholarGoogle Scholar | 24062194PubMed |

Zhang, Q, Wang, S-M, Yao, P-B, et al. (2015). Effects of l-carnitine on follicular survival and graft function following autotransplantation of cryopreserved-thawed ovarian tissues. Cryobiology 71, 135–140.
Effects of l-carnitine on follicular survival and graft function following autotransplantation of cryopreserved-thawed ovarian tissues.Crossref | GoogleScholarGoogle Scholar | 25956417PubMed |

Zheng, H-l, Zhang, H-y, Zhu, C-l, et al. (2021). l-Carnitine protects against tacrolimus-induced renal injury by attenuating programmed cell death via PI3K/AKT/PTEN signaling. Acta Pharmacologica Sinica 42, 77–87.
l-Carnitine protects against tacrolimus-induced renal injury by attenuating programmed cell death via PI3K/AKT/PTEN signaling.Crossref | GoogleScholarGoogle Scholar | 32555441PubMed |

Zimmerman, BJ, and Granger, DN (1992). Reperfusion injury. Surgical Clinics of North America 72, 65–83.
Reperfusion injury.Crossref | GoogleScholarGoogle Scholar |