Evaluation of Protective Effects of Folinic Acid and Gonadotropin-Releasing Hormone Agonist and Antagonist Against Methotrexate Toxicity in Rats

Objective: A single dose of the folic acid antagonist methotrexate (MIX) is commonly used in ectopic pregnancy. However, the safety of MTX therapy on the ovarian reserve is still controversial. This study aimed to evaluate the use of folinic acid, a gonadotropin-releasing hormone (GnRH) antagonist, and a GnRH agonist on single-dose MTX-induced rat ovarian toxicity. Methods: A total of 40 Wistar albino rats were randomly divided into five equal groups. Then, all rats were administered MTX intramuscularly. While only physiological saline solution was administered to the control group, only MTX was administered to the MTX group. After 24 h of MTX administration, the MTX + leucovorin group received leucovorin. The MTX + GnRHa group received triptorelin acetate and MTX simultaneously. The MTX + GnRHant group received cetrorelix acetate with MTX. Results: The anti-mullerian hormone (AMH) level was similar in the control, MTX, MTX + GnRHa, MTX + GnRHant, and MTX + folinic acid groups. The number of primordial follicles was lower in the MTX group than in the control group (p=0.004), whereas this number in the other groups was similar to that in the control group. AMH levels in the MTX + folinic acid (p=0.001) and MTX + GnRHa (p=0.002) groups were higher than those in the MTX group. The number of primordial, primary, secondary and tertiary follicles was significantly higher in the MTX + folinic acid, MTX + GnRHa, and MTX + GnRHant groups than that in the MTX group. Conclusions: To the best of our knowledge, this is the first experimental study that can be benefited to minimize the damaging impacts of singledose MTX administration on ovarian reserve and AMH levels. Although the negative impact of single-dose MTX on ovarian reserve is known, our results show that this effect can be minimized by the concurrent administration of GnRHa, GnRHant, or folinic acid. The findings of the present study need to be confirmed with more extensive laboratory studies as well as with randomized controlled clinical studies