Objective To observe the therapeutic effect of a gonadotropin-releasing hormone agonist combined with various doses of estrogen in a rat model of endometriosis and the recurrence of endometriosis. Methods Fifty-one rats with endometriosis were established by autologous transplantation of the uterus and then randomly divided into five groups: control group (n = 10), 1 mg/ kg NS subcutaneous injection once; treatment groups, add-back group Ⅰ (low-dose estrogen group, n = 10), add-back group Ⅱ (medium-dose estrogen group, n = 10), add-back group Ⅲ (high-dose estrogen group, n =10), GnRH-a group (n =11), 1 mg/ kg leuprolide subcutaneous injection once. Add-back groups Ⅰ- Ⅲ were administered various doses of estradiol valerate at week 2 (25, 50, and 100 μg/ kg) and the GnRH-a group was administered 3 mL NS per rat once a day by gavage at week 2. At weeks 3 and 6 after intragastric administration of estradiol valerate, a laparotomy was performed to measure the volume of endometriosis. The protein levels of tumor necrosis factor-α(TNF-α) and steroidogenic acute regulatory (StAR) protein were detected by immunohistochemistry. The levels of serum CA125 were detected by an enzyme-linked immunosorbent assay. Results Before the treatments, there was no significant difference in the volume of ectopic lesions in each group ( P >0. 05). At week 4, the mean volumes of ectopic lesions in the treatment groups were significantly reduced compared with that of the control group ( P < 0. 05). At week 7, the volumes of ectopic lesions in add-back Ⅱ and Ⅲ groups were significantly higher than those in the add-back Ⅰ and GnRH-a groups ( P < 0. 05). Before the treatments, there was no significant difference in the expression of TNF-α and StAR in ectopic lesions of each group ( P >0. 05). At week 4 of the treatments, the TNF-α and StAR expression in ectopic lesions of treatment groups was significantly lower than that in the control group ( P <0. 05). At week 7, TNF-α and StAR expression in add-back Ⅱ and Ⅲ groups was significantly higher than that in the add-back group Ⅰ and GnRH-a groups ( P <0. 05). Before the treatments, there was no significant difference in the serum level of CA125 in the each group ( P >0. 05). At week 4, the serum level of CA125 in the treatment groups was significantly lower than that in the control group( P <0. 05). At week 7, the serum levels of CA125 in the add-back Ⅱ and Ⅲ groups were significantly higher than those in the add-back group Ⅰ and GnRH-a groups ( P < 0. 05). Conclusions GnRH-a combined with low-dose estrogen causes marked suppression of endometriosis in the rat. Replacement therapy by medium and high doses of estrogen may stimulate rapid recurrence of endometriotic implant growth induced by TNF-α and StAR.