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

Ronald W Lewis, K. J. Dowling, A. V. Schally

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Abstract

Possible protective effects of the agonist [D-Trp6]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. The average baseline count for the animals ranged from 95.7 x 106 to 585.7 x 106 sperm per ml with 90% normal forms and 85% motility with excellent rapid forward progression. After baseline evaluations, two of the animals were treated with daily subcutaneous injections of 0.5 mg of the agonist [D-Trp6]LH-RH. There was an initial rise in serum testosterone after 1 week, but testosterone fell to castration values at 1 month and continued at these levels during treatment with the agonist. There was also an initial rise in sperm concentration 1 month after treatment was started, but after 2 months the animals were azoospermic. After 13 weeks of therapy with [D-Trp6]LH-RH, these two baboons and a third untreated control animal were given cyclophosphamide at a dose of about 3 mg/kg of body weight per day for 4 months. The two animals pretreated with [D-Trp6]LH-RH, continued to receive this agonist until 1 week after the last dose of Cytoxan. In one of the two baboons treated with Cytoxan and the LH-RH agonist, the white blood count fell below 4000 pr μl, and the dose of Cytoxan had to be reduced to 1.5 mg/kg per day for 12 days. The control animal developed azoospermia after 4 months of treatment with cyclophosphamide, and serum testosterone increased while sperm count decreased. Four weeks after the agonist was stopped, serum testosterone in both animals pretreated with [D-Trp6]LH-RH returned to normal levels. The control animal showed a small amount of nonmotile sperm 2.5 months after cessation of treatment, but after 9 months remains oligospermic with poor sperm motility. In one of the animals treated with LH-RH agonist, semen analysis returned to normal pretreatment values 8 months after withdrawal of treatment. The other animal remains oligospermic 10 months after therapy, but the motility is improving. These preliminary results suggest that treatment with LH-RH agonist might decrease the gonadal damage caused by some chemotherapeutic agents.

Original languageEnglish (US)
Pages (from-to)2975-2979
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume82
Issue number9
DOIs
StatePublished - Jan 1 1985

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Protective Agents
Papio
Gonadotropin-Releasing Hormone
Tryptophan
Cyclophosphamide
Testosterone
Spermatozoa
Therapeutics
Papio anubis
Serum
Azoospermia
Withholding Treatment
Semen Analysis
Sperm Count
Sperm Motility
Castration
Subcutaneous Injections
Semen
Primates
Reference Values

ASJC Scopus subject areas

  • General

Cite this

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title = "D-Tryptophan-6 analog of luteinizing hormone-releasing hormone as a protective agent against testicular damage caused by cyclophosphamide in baboons",
abstract = "Possible protective effects of the agonist [D-Trp6]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. The average baseline count for the animals ranged from 95.7 x 106 to 585.7 x 106 sperm per ml with 90{\%} normal forms and 85{\%} motility with excellent rapid forward progression. After baseline evaluations, two of the animals were treated with daily subcutaneous injections of 0.5 mg of the agonist [D-Trp6]LH-RH. There was an initial rise in serum testosterone after 1 week, but testosterone fell to castration values at 1 month and continued at these levels during treatment with the agonist. There was also an initial rise in sperm concentration 1 month after treatment was started, but after 2 months the animals were azoospermic. After 13 weeks of therapy with [D-Trp6]LH-RH, these two baboons and a third untreated control animal were given cyclophosphamide at a dose of about 3 mg/kg of body weight per day for 4 months. The two animals pretreated with [D-Trp6]LH-RH, continued to receive this agonist until 1 week after the last dose of Cytoxan. In one of the two baboons treated with Cytoxan and the LH-RH agonist, the white blood count fell below 4000 pr μl, and the dose of Cytoxan had to be reduced to 1.5 mg/kg per day for 12 days. The control animal developed azoospermia after 4 months of treatment with cyclophosphamide, and serum testosterone increased while sperm count decreased. Four weeks after the agonist was stopped, serum testosterone in both animals pretreated with [D-Trp6]LH-RH returned to normal levels. The control animal showed a small amount of nonmotile sperm 2.5 months after cessation of treatment, but after 9 months remains oligospermic with poor sperm motility. In one of the animals treated with LH-RH agonist, semen analysis returned to normal pretreatment values 8 months after withdrawal of treatment. The other animal remains oligospermic 10 months after therapy, but the motility is improving. These preliminary results suggest that treatment with LH-RH agonist might decrease the gonadal damage caused by some chemotherapeutic agents.",
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N2 - Possible protective effects of the agonist [D-Trp6]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. The average baseline count for the animals ranged from 95.7 x 106 to 585.7 x 106 sperm per ml with 90% normal forms and 85% motility with excellent rapid forward progression. After baseline evaluations, two of the animals were treated with daily subcutaneous injections of 0.5 mg of the agonist [D-Trp6]LH-RH. There was an initial rise in serum testosterone after 1 week, but testosterone fell to castration values at 1 month and continued at these levels during treatment with the agonist. There was also an initial rise in sperm concentration 1 month after treatment was started, but after 2 months the animals were azoospermic. After 13 weeks of therapy with [D-Trp6]LH-RH, these two baboons and a third untreated control animal were given cyclophosphamide at a dose of about 3 mg/kg of body weight per day for 4 months. The two animals pretreated with [D-Trp6]LH-RH, continued to receive this agonist until 1 week after the last dose of Cytoxan. In one of the two baboons treated with Cytoxan and the LH-RH agonist, the white blood count fell below 4000 pr μl, and the dose of Cytoxan had to be reduced to 1.5 mg/kg per day for 12 days. The control animal developed azoospermia after 4 months of treatment with cyclophosphamide, and serum testosterone increased while sperm count decreased. Four weeks after the agonist was stopped, serum testosterone in both animals pretreated with [D-Trp6]LH-RH returned to normal levels. The control animal showed a small amount of nonmotile sperm 2.5 months after cessation of treatment, but after 9 months remains oligospermic with poor sperm motility. In one of the animals treated with LH-RH agonist, semen analysis returned to normal pretreatment values 8 months after withdrawal of treatment. The other animal remains oligospermic 10 months after therapy, but the motility is improving. These preliminary results suggest that treatment with LH-RH agonist might decrease the gonadal damage caused by some chemotherapeutic agents.

AB - Possible protective effects of the agonist [D-Trp6]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. The average baseline count for the animals ranged from 95.7 x 106 to 585.7 x 106 sperm per ml with 90% normal forms and 85% motility with excellent rapid forward progression. After baseline evaluations, two of the animals were treated with daily subcutaneous injections of 0.5 mg of the agonist [D-Trp6]LH-RH. There was an initial rise in serum testosterone after 1 week, but testosterone fell to castration values at 1 month and continued at these levels during treatment with the agonist. There was also an initial rise in sperm concentration 1 month after treatment was started, but after 2 months the animals were azoospermic. After 13 weeks of therapy with [D-Trp6]LH-RH, these two baboons and a third untreated control animal were given cyclophosphamide at a dose of about 3 mg/kg of body weight per day for 4 months. The two animals pretreated with [D-Trp6]LH-RH, continued to receive this agonist until 1 week after the last dose of Cytoxan. In one of the two baboons treated with Cytoxan and the LH-RH agonist, the white blood count fell below 4000 pr μl, and the dose of Cytoxan had to be reduced to 1.5 mg/kg per day for 12 days. The control animal developed azoospermia after 4 months of treatment with cyclophosphamide, and serum testosterone increased while sperm count decreased. Four weeks after the agonist was stopped, serum testosterone in both animals pretreated with [D-Trp6]LH-RH returned to normal levels. The control animal showed a small amount of nonmotile sperm 2.5 months after cessation of treatment, but after 9 months remains oligospermic with poor sperm motility. In one of the animals treated with LH-RH agonist, semen analysis returned to normal pretreatment values 8 months after withdrawal of treatment. The other animal remains oligospermic 10 months after therapy, but the motility is improving. These preliminary results suggest that treatment with LH-RH agonist might decrease the gonadal damage caused by some chemotherapeutic agents.

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