Acute depletion of murine primordial follicle reserve by gonadotropin-releasing hormone antagonists

Objective: To examine the effects of GnRH antagonists on preantral follicle survival in vivo and to investigate whether GnRH antagonist use during cyclophosphamide treatment would protect the ovary and preserve primordial follicle survival in a murine model. Design: Prospective basic research study. Setting: Research laboratory in an academic medical center. Animal(s): Adult C57B1/6 mice (5 to 6 weeks old). Intervention(s): Mice received either a single injection of GnRH agonist (leuprolide acetate) on study day -10 or injections of the GnRH antagonist (antide or cetrorelix) on study days -3 and 0. Some animals also received the chemotherapeutic agent cyclophosphamide on day 0. All animals were killed by CO2 asphyxiation on day 7. To examine direct vs. indirect effects, some mice received GnRH antagonist under the bursa of one ovary, with the contralateral ovary receiving vehicle. Ovaries were fixed in Kahle's solution; 7-mu m tissue sections were stained with Lillie s allochrome, and preantral follicles were counted on every fifth section. Main Outcome Measure(s): Numbers of primordial, primary, and secondary follicles. Result(s): Systemic administration of both GnRH antagonists caused a significant destruction of primordial follicles compared with control mice. Similar results were obtained whether the antagonists were administered systemically or directly to the ovary. Gonadotropin-releasing hormone agonist had no effect on primordial follicle numbers by itself but reduced the follicular depletion caused by cyclophosphamide. Concluslon(s): In contrast to the effects of GnRH agonists to reduce chemotherapeutic destruction of primordial follicles. GnRH antagonists do not protect the ovary from the damaging effects of cyclophosphamide. More importantly. GnRH antagonists alone deplete primordial follicles in this murine model, likely through a direct effect on the ovary. Whether these observations apply to other species requires further study. ((c) 2005 by American Society for Reproductive Medicine.)