Temsirolimus and anti-Müllerian hormone protect fertility and the ovarian reserve against chemotherapy-induced damage in a murine model.

Objective: To investigate the effects of temsirolimus and recombinant anti-Müllerian hormone (AMH) on fertility and the ovarian reserve when associated with chemotherapy.

Design: Thirty-seven female mice were assigned to one of three treatment groups: (i) control group; (ii) chemotherapy group; and (iii) gonadoprotection group. Five weeks after treatment, the mice underwent ovarian stimulation and were mated with males to evaluate residual fertility. Two days after mating, the animals were euthanized for embryo collection, and ovaries were retrieved to assess the ovarian reserve and follicle damage.

Setting: Academic research center.

Subject: Thirty-seven Naval Medical Research Institute mice.

Exposure: The control group (n=10) was given a 100 μL injection of phosphate-buffered saline. The chemotherapy group (n=13) received a single 100 μL injection of chemotherapy (120 mg/kg cyclophosphamide and 12 mg/kg busulfan). The gonadoprotection group (n=14) was administered five injections of 5mg/kg temsirolimus over one week prior to chemotherapy, followed by a chemotherapy injection, then five injections of 5μg recombinant AMH over the next 24 hours.

Main outcome measures: Embryo count, follicle count and morphology, and immunostaining for apoptosis (cleaved caspase-3), follicle activation (phospho-Akt), and proliferation (Ki67).

Results: The control group showed the highest mean number of retrieved embryos (41.40 ± 14.74), closely followed by the gonadoprotection group (36.27 ± 17.22), while the chemotherapy group exhibited a significant reduction (20.63 ± 12.12) compared to both groups. Regarding the ovarian reserve, the control group showed the highest total follicle count (897.4 ± 392.8), with no difference compared to the gonadoprotection group (714.4 ± 283.9), but there was a significant decline in the chemotherapy group (320.7 ± 145.5) compared to both groups. In terms of follicle apoptosis and activation, no significant difference was observed between groups. Follicle proliferation rates were significantly higher in the chemotherapy group (59.38% ± 14.67%) than in the control group (20.72% ± 10.52%), but gonadoprotective treatment did curtail follicle proliferation (42.23% ± 18.37%) compared to the chemotherapy group.

Conclusion: Our findings suggest that temsirolimus and AMH show promise as gonadoprotective agents, potentially protecting the ovarian reserve against chemotherapy and thereby preserving fertility. This could offer patients who cannot benefit from currently available techniques brand new fertility preservation options.