Protective effects of analogs of luteinizing hormone-releasing hormone against chemotherapy-induced testicular damage in rats.

Abstract

Possible protective effects of analogs of luteinizing hormone-releasing hormone (LH-RH) against testicular damage caused by various cytotoxic agents were investigated in rats. The agonist per day, and the antagonist was injected s.c. at a dose of 1000 ,ug per kg of body weight per day for the first 3 weeks and, thereafter, at a dose of 500 ,ug per kg of body weight per day. After a recovery period of 3 months, most seminiferous tubules in the antagonist-treated group showed a normal morphology, while patches of tubules in the agonist-treated group continued to show some suppression of spermatogenesis. Administration of busulfan, cisplatin, or cyclophosphamide produced only a reversible testicular injury, and pretreatment with LH-RH analogs seemed to temporarily enhance the tubular damage. Administration of procarbazine (200 mg per kg of body weight per week for 6 weeks) resulted in decreased testicular weights and increased serum LH levels 1 and 3 months after the discontinuation of treatment. The histology showed severe diffuse damage to seminiferous tubules. The germinal cells completely disappeared and the Sertoli cells were markedly degenerated. This damage was not restored even after a recovery period of 5 months. Some animals were pretreated for 6 weeks with the agonist or antagonist and then received procarbazine for 6 weeks while administration of analogs was continued. In these animals, the decrease in testicular weights and increase in serum LH levels after procarbazine were less marked than in the group not pretreated with the analogs. Three and 5 months after cessation of treatment, a large number of tubules showed a complete restoration of structural morphology in 30-45% of the animals that received procarbazine and the LH-RH agonist or antagonist. These results indicate that pretreatment with LH-RH analogs may protect testes against damage caused by some cytotoxic agents.GlyIn recent years, cytotoxic chemotherapy has led to an increased number of sustained remissions in patients with malignant tumors. However, chemotherapy, particularly with alkylating agents, can produce damage to actively dividing tissues (such as testicular) and consequently many patients become sterile (1-4). Since dividing cells of testis are more sensitive to cytotoxic agents than resting cells (1-3), suppression of hypophysial-gonadal axis before chemotherapy might allow for return of normal spermatogenesis (5).Chronic administration of agonists of luteinizing hormonereleasing hormone (LH-RH), after an initial period of stimulation, induces down-regulation of receptors, desensitization of pituitary gonadotrophs, and suppression of gonads (5-7). The inhibition of male reproductive functions in human beings (8-10) and rats (11-13) is reversible after treatment with LH-RH agonists is discontinued.Whereas repeated administration of LH-RH agonists is required to reduce the levels of LH, follicle-stimulating hormone (FSH), and sex steroids, an immediate inhibition can be obtained after the first injection of LH-RH antago...

Protection of rat spermatogenic epithelium from damage induced by procarbazine chemotherapy

“…In contrast to the findings of Rivier et al (1979), we noted greater permanent toxicity from GnRH analogue treatment in rats, an effect that has also been reported by others (Lefebvre et al, 1984). Pogach et al (1988) noted partial protection of spermatogenesis in procarbazine treated rats only if testosterone was co-administered with a GnRh antagonist, while Karashima et al (1988) achieved protection using a GnRH agonist alone.…”

Protective effects of D-Trp6-luteinising hormone-releasing hormone microcapsules against cyclophosphamide-induced gonadotoxicity in female rats

“…In addition, we have developed prototypes of sustained delivery systems consisting of microcapsules of our LH-RH antagonist SB-75 (Csernus et al, 1990). Since, in patients afflicted with a malignant disease, chemotherapy may have to be started soon after the diagnosis is made, LH-RH antagonists may be preferred over the agonists for induction of gonadal inhibition, considering the rapidity of their suppressive action (Karashima et al, 1988;Schally et al, 1980;Schally, 1989 …”

“…However, the incidence of ovarian dysfunction after chemotherapy can reach 80% among women treated for Hodgkin's disease (Chapman et al, 1979). Several studies on gonadal protection against the damage induced by cytotoxic drugs have been performed in males of different species (Glode et al, 1982;Karashima et al, 1988;Lewis et al, 1985;Nseyo et al, 1985), but the information about females is limited. Ataya et al (1985) reported that administration of the LH-RH agonist D-Leu6-des-Gly'0-NH2-LH-RH ethylamide before and during chemotherapy was able to prevent the ovarian follicle loss induced by cyclophosphamide in the rat.…”

“…This inhibitory effect is reversible, and gonadal recovery occurs after treatment with LH-RH agonists is discontinued. This approach has been suggested as a possible protective method against gonadal damage induced by chemotherapeutic drugs and radiation (Glode et al, 1982;Jarrel et al, 1987b;Karashima et al, 1988;Lewis et al, 1985;Schally et al, 1987;Schally, 1989).…”

“…Since cytotoxic drugs affect more tissues with a rapid cellular turnover, it has been suggested that a state of induced gonadal inhibition during the exposure to chemotherapy may protect the gonads (Karashima et al, 1988;Rivkees & Crawford, 1988). Chronic administration of agonists of luteinising hormone releasing hormone (LH-RH), after an initial period of stimulation, induces downregulation of the receptors, desensitisation of pituitary gonadotrophs and suppression of the gonadal functions (Schally et al, 1980;Schally, 1989).…”