GnRH analog, leuprorelin acetate, promotes regeneration of rat spermatogenesis after severe chemical damage

Abstract

Background: Future fertility is a major concern for cancer patients who undergo intensive chemotherapy. There has been controversy about whether hormonal treatments may have protective effects against the severe spermatogenic damage caused by chemotherapy or irradiation. Recently, it has been proposed that gonadotrophin-releasing hormone (GnRH) analogs administered after testicular damage stimulate the recovery of spermatogenesis. In this study, we have investigated the effects of GnRH agonist, leuprorelin, on the damage to spermatogenesis induced by busulfan. Methods: Fisher rats were treated with busulfan, 25 mg/kg, intraperitoneally. The effects of subcutaneous injections of leuprorelin before or after treatment were evaluated histologically 18 weeks later. Results:The percentage of 'recovered' seminiferous tubules was 27.7 ± 12.6% in control rats without leuprorelin and 26.9 ± 10.2% in rats with leuprorelin injected 4 weeks before busulfan. Rats in both groups showed poor recovery of spermatogenesis with an increase of intratesticular fluid. However, rats treated with leuprorelin three times (4 weeks apart) after busulfan showed an improvement of up to 56.5 ± 12.0% (P < 0.05). A focal but massive necrotic lesion in the testis was observed only in this group of rats. Conclusions:The results demonstrated that leuprorelin administered after chemical testicular damage enhanced the recovery of spermatogenesis. At the same time, a possible significant side-effect of leuprorelin was noted.

Preventive role of exogenous testosterone on cisplatin-induced gonadal toxicity: an experimental placebo-controlled prospective trial

“…They found that the administration of GnRH agonist during cyclophosphamide chemotherapy may protect spermatogenesis. These promising results were reproduced 20 years later by Udagawa et al (15).…”

Increment of Murine Spermatogonial Cell Number by Gonadotropin-Releasing Hormone Analogue Is Independent of Stem Cell Factor c-kit Signal1

“…The reduction of gonadotropin secretion results in lower testosterone levels in testes, leading to the inhibition of spermatogenesis [40], particularly in postmeiotic phase [4,41,42]. In contrast, recent studies have shown that GnRH-analogues stimulate regeneration of spermatogenesis after testicular damage caused by irradia- tion or chemical toxins [3,6,8]. A study using irradiated testis model has suggested that GnRH-antagonist reduces spermatogonial apoptosis, thus increasing the number of spermatogonia [9].…”

“…This result was unexpected because the predominant effect of GnRH-analogues had been believed to inhibit spermatogenesis, as GnRH-analogue administration reduces LH and FSH, thereby suppressing testosterone level [4,5]. Subsequent studies, however, have confirmed that GnRH-analogues, both agonist and antagonist, can promote the regeneration process of spermatogenesis following testicular injuries by irradiation or cancer chemotherapy drugs [6][7][8]. Another study showed that GnRH-antagonist enhanced the proliferation and differentiation of type A spermatogonia, probably due to reduced levels of apoptotic cell death [9].…”

Hormonal suppression for fertility preservation in males and females

“…Nevertheless, when additional time without further suppressive treatment was allowed before the rats were killed, all tubules showed almost complete spermatogenic recovery, sperm counts increased, and the fertility of the rats significantly increased (Meistrich et al 2001). This phenomenon appears to be quite general: posttreatment with GnRH agonists or antagonists, with or without antiandrogen, low-dose systemic testosterone, estradiol, or hypophysectomy are all effective at stimulating recovery (Shetty et al 2002, and recovery has been stimulated following gonadal toxicity from anticancer agents, such as radiation, procarbazine (Meistrich et al 1999), or busulfan (Udagawa et al 2001), and environmental toxicants, such as hexanedione (Blanchard et al 1998) or dibromochloropropane (Meistrich et al 2003), an indenopyridine compound (Hild et al 2001), or heat treatment (Setchell et al 2001). The endogenous hormone primarily responsible for the inhibition of spermatogonial differentiation in toxicant-treated rats was testosterone, although follicle-stimulating hormone (FSH) also had a minor inhibitory effect , and other exogenously administered androgens were also inhibitory (Shetty et al 2002).…”