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.

Antiapoptotic effect of l-carnitine on testicular irradiation in rats

“…Infertility after irradiation is caused by the spermatogonia undergoing apoptosis instead of differentiation (Boekelheide et al 2005). The ability of the testis to recover spermatogenesis depends on the survival of some stem spermatogonia and their ability to repopulate the testis with differentiating cells (Shetty and Meistrich 2005).…”

Humanin protects against chemotherapy-induced stage-specific male germ cell apoptosis in rats

“…In prior studies, GnRH antagonist plus the anti-androgen flutamide treatment suppressed testosterone levels and action in rats and protected spermatogonial stem cell damage induced by CP or irradiation and restored spermatogenesis and fertility (Meistrich et al ., 1995; Shetty & Meistrich, 2005). However, when the same principle was translated to non-human primates, suppression of testosterone by GnRH antagonist did not restore spermatogenesis induced by irradiation indicating species differences in testicular responses to GnRH antagonist and irradiation (Boekelheide et al ., 2005; Shetty & Meistrich, 2005). The observation that CP-induced apoptosis of germ cells requires Leydig cells and testosterone does not distract from the principal point of this manuscript that HN protects against germ cell apoptosis in the absence of Leydig cells and despite the fact that intratesticular testosterone levels are very low.…”

Cancer treatment and gonadal function: experimental and established strategies for fertility preservation in children and young adults

“…Approaches to protecting the gonad in situ include altering the hormonal milieu to render the gonad insensitive to the effects of cancer treatment. Whilst studies in rodents utilising GnRH analogues and/or sex steroids offered much promise (reviewed in 39 ) such approaches have failed to offer protection to the gonad in primates 93,94 and humans (reviewed in 95 ). Limited data from rodent studies are also available on the use of pharmacological agents for fertility preservation in males 96 .…”