Prevention of cyclophosphamide-induced ovarian damage by concomitant administration of GnRHa in mice: A dose-dependent relationship?

Objective(s): This experimental study investigates the dose-related effects of cyclophosphamide (Cy) on primordial follicular reserve in young mice, and examines whether the concomitant administration of a gonadotropin-releasing hormone agonist (GnRHa) may protect gonadal reserve, even at different doses of Cy.

Methods: Forty sexually mature virginal Balb/c mice aged five to six weeks were administered different doses (0, 50, 75,100 mg/kg) of Cy. Another 40 animals were treated with increasing doses (0, 50, 75, 100 mg/kg) of Cy in combination with GnRHa. GnRHa treatment was initiated one week prior to chemotherapy and also continued after chemotherapy for one week. The ovaries were removed seven days after Cy administration and the total number of primordial follicles in both ovaries was counted.

Results: Primordial follicular destruction occurred at all levels of Cy exposure. There was a positive correlation between increasing doses of Cy and higher proportion of follicular loss (p < 0.0001). GnRHa was not able to protect against the chemotherapy-induced negative effect on primordial follicular count at low doses (50 mg/kg and 75 mg/kg). Mean +/- SD primordial follicle count in the 100 mg/kg Cy-treated group was significantly lower than in the 100 mg/kg Cy + GnRHa treatment group (73.9 +/- 33.1 vs 89 +/- 17.9, p = 0.047).

Conclusion: Our data suggest a possible ovarian protective effect of GnRHa cotreatment only at high doses of Cy treatment. However, in spite of co-administration of GnRHa, loss of primordial follicular reserve occurred at all doses of Cy in mice.

Chemotherapy; GnRHa; Ovarian toxicity; Premature ovarian failure; Primordial follicles; Cyclophosphamide; Primordial follicular reserve

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