Protection From Cyclophosphamide-Induced Testicular Damage With an Analogue of Gonadotropin-Releasing Hormone

Glode, L. Michael; Robinson, Julie; Gould, Stanley F.

doi:10.1016/s0140-6736(81)92301-1

Cited by 217 publications

(24 citation statements)

References 14 publications

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“…A report that administration of the agonist Buserelin failed to preserve fertility in patients subjected to chemotherapy may have been due to inadequate doses and short duration of treatment (26). In view of our findings (13,17) and those of others (22,23) that LH-RH analogs can protect testes and ovaries (27) from chemotherapy and/or irradiation, additional studies are required to determine optimal dosages and duration of treatment for possible clinical applications. Since in patients afflicted with various malignancies, chemotherapy or radiation 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 their rapidity of suppressive action.…”

Section: Discussionmentioning

confidence: 67%

“…We used four different cytostatic agents and found that procarbazine, a hydrazine-derived antineoplastic agent, produced the greatest testicular damage in rats, which continued up to 5 months after the treatment, in agreement with previous reports (20,21). On the other hand, although cisplatin (22, §) and cyclophosphamide (20,22,23) were reported to cause injuries to testis, in various species, these two agents, as well as busulfan, produced only reversible damage to seminiferous tubules.…”

Section: Discussionmentioning

confidence: 99%

“…Glode et al (23) The successful use of LH-RH antagonists in rats for prevention of testicular damage induced by chemotherapy or radiation may have clinical implications. We observed that a LH-RH antagonist protected rat testes from the permanent damage inflicted by x-irradiation more effectively than the LH-RH agonist (13).…”

Section: Discussionmentioning

confidence: 99%

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

Karashima¹,

Zalatnai²,

Schally³

1988

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

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

Karashima¹,

Zalatnai²,

Schally³

1988

Proc. Natl. Acad. Sci. U.S.A.

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“…However, these conclusions were based on only two treated mice (31), and more experimental work is needed to confirm and extend these initial findings.…”

mentioning

confidence: 96%

“…Recently Glode et al (31) reported that temporary inhibition of the pituitary-gonadal axis by administration of [DLeu6]LH-RH ethylamide protected mouse testes from cyclophosphamide-induced damage (31). However, these conclusions were based on only two treated mice (31), and more experimental work is needed to confirm and extend these initial findings.…”

mentioning

confidence: 99%

D-Tryptophan-6 analog of luteinizing hormone-releasing hormone as a protective agent against testicular damage caused by cyclophosphamide in baboons.

Lewis

Dowling

1985

Proc. Natl. Acad. Sci. U.S.A.

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Possible protective effects of the agonist [D-TrpV]LH-RH (the D-tryptophan-6 analog of luteinizing hormone-releasing hormone) against testicular damage caused by cyclophosphamide (Cytoxan) were investigated in subhuman primates. Three adult male baboons (Papio anubis) were first subjected to normal semen evaluation by using electroejaculation. There may be differences in the sensitivity of the prepubertal, pubertal, and adult testis to chemotherapy with alkylating agents (1-3, 8). The prepubertal testis may be more resistant to the effects of alkylating agents than is the adult gonad (2). Prepubertal boys and boys in early puberty treated with cyclophosphamide for nephrosis appear to have normal follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels after therapy as well as normal levels of testosterone. These effects seem to be also dependent on the dosage and duration of therapy (1,3,8). In one study cyclophosphamide, which was used for chemotherapy in a dose of 50-100 mg daily in adult males for 4 months, induced azoospermia (3). In another study with cyclophosphamide in children with nephrosis, results showed two distinct patterns. Four males who received 2-4 mg/kg of body weight per day for 49-60 days had normal semen, while four patients who received 2-5 mg/kg per day for 89-489 days showed azoospermia.LH-releasing hormone (LH-RH) agonists and antagonists effectively but reversibly inhibit the pituitary-gonadal function and fertility in animals (9-20). Chronic administration of superactive agonists of LH-RH produces dramatic inhibitory effects through a process of down-regulation of receptors, desensitization of pituitary gonadotrophs, and suppression of gonads (9)(10)(11)(12)(13)(14)(15)20). In male animals this is manifested by a decrease in the weights of testes, seminal vesicles, and prostate; inhibition of spermatogenesis; and a decrease in plasma LH, FSH, and testosterone levels (9-11, 13, 15, 21-27). In men, a persistent suppression of Leydig-cell function manifested by a decrease in serum testosterone and dihydrotestosterone levels and inhibition of spermatogenesis have been observed after chronic administration of the agonists [D-Trp6]LH-RH (the D-tryptophan-6 analog of LH-RH) or [D-Ser(But)6]des-(Gly-NH2)10-LH-RH ethylamide (9-11, 16, 21, 22, 28, 29). The inhibition of reproductive functions in animals and human beings of both sexes by agonists of LH-RH is reversible and fertility is restored after treatment is stopped (9-11, 14, 16, 19, 21, 22, 30 2975The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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Gonadal Activity and Chemotherapy-Induced Gonadal Damage

Redman¹,

Bajorunas²

1988

JAMA

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Protection From Cyclophosphamide-Induced Testicular Damage With an Analogue of Gonadotropin-Releasing Hormone

Cited by 217 publications

References 14 publications

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

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

D-Tryptophan-6 analog of luteinizing hormone-releasing hormone as a protective agent against testicular damage caused by cyclophosphamide in baboons.

Gonadal Activity and Chemotherapy-Induced Gonadal Damage

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