title: Gonadotropin-releasing hormone antagonist (Cetrorelix) therapy fails to protect nonhuman primates (Macaca arctoides) from radiation-induced spermatogenic failure.
abstract: Treatment of men of reproductive age with radiation or alkylating agents often produces prolonged azoospermia. We previously demonstrated that suppression of testosterone (T) with gonadotropin-releasing hormone (GnRH) analogs restored spermatogenesis following atrophy induced by radiation or chemotherapy in rats. This study tested whether GnRH antagonist therapy could reverse radiation-induced testicular injury in primates with a similar protocol. Adult male stump-tailed macaques were given either 6.7 Gy radiation to the testis alone, 6.7 Gy radiation combined with GnRH-antagonist treatment starting on the day of exposure, or daily injections of the GnRH antagonist Cetrorelix for 3 months alone and were monitored for 18 months. Cetrorelix alone produced a 20-40-week fully reversible suppression of serum T, but although spermatogenic recovery was incomplete, 40%-90% of tubules contained differentiating germ cells. Following radiation alone, testis volumes were reduced to approximately 28% and sperm counts to less than 1% of pretreatment values. A biopsy at 18 months after radiation showed that only 3.0% of seminiferous tubule cross sections had germ cells. In irradiated animals that received GnRH antagonist, testis volumes were reduced to 18% of pretreatment volume, and at 18 months, only 1.9% of seminiferous tubule cross sections contained germ cells. Inhibin B values were reduced to 10% and 3% of pretreatment levels in the radiation-only and the radiation plus GnRH antagonist groups, respectively. Species differences exist in the testicular response to radiation, GnRH antagonist therapy, or both, so that rescue protocols that were successful in rodents might not work in primates.
authors.affiliation: Department of Pathology and Laboratory Medicine, Brown University, Box G-E504, Providence, RI 02912, USA. Kim_Boekelheide@Brown.edu
authors.forename: Kim
authors.initials: K
authors.lastname: Boekelheide
authors.forename: Heidi A
authors.initials: HA
authors.lastname: Schoenfeld
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Hall
authors.forename: Connie C
authors.initials: CC
authors.lastname: Weng
authors.forename: Gunapala
authors.initials: G
authors.lastname: Shetty
authors.forename: John
authors.initials: J
authors.lastname: Leith
authors.forename: James
authors.initials: J
authors.lastname: Harper
authors.forename: Mark
authors.initials: M
authors.lastname: Sigman
authors.forename: David L
authors.initials: DL
authors.lastname: Hess
authors.forename: Marvin L
authors.initials: ML
authors.lastname: Meistrich
mesh_terms: D000818:Animals; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology; D008251:Macaca; D008297:Male; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D012661:Semen / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D013091:Spermatogenesis / Q000187:drug effects* / Q000528:radiation effects*
chemical_list: D006727:Hormone Antagonists; D011837:Radiation-Protective Agents; D007987:Gonadotropin-Releasing Hormone; C062876:cetrorelix