Testicular function in prepubertal and pubertal male patients treated with cyclophosphamide for nephrotic syndrome

Penso, Jeffrey S.; Lippe, Barbara M.; Ehrlich, Richard M.; Smith, F.

doi:10.1016/s0022-3476(74)80758-4

Cited by 94 publications

(12 citation statements)

References 25 publications

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“…Several studies also pointed to the fact that reduced sperm counts concur with decreased motility and increased proportions of abnormal forms [67,93,99]. Leydig cells appeared to remain present [73,124], and were functionally not affected [103,128]. Testicular atrophy was observed by others [73,99,110], but it was shown that normal histology may miss functional damage [109,121].…”

Section: Gonadal Toxicitymentioning

confidence: 99%

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A meta-analysis of cytotoxic treatment for frequently relapsing nephrotic syndrome in children

Latta

Schnakenburg

Ehrich

2001

Pediatric Nephrology

217

145

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For over 30 years cyclophosphamide (CYC) and chlorambucil (CHL) have been used to treat children with relapsing steroid-sensitive nephrotic syndrome (SSNS). A meta-analysis on treatment protocols, efficacy, and side effects of CYC and CHL was performed from the literature. Thirty-eight studies comprising 1,504 children and 1,573 courses of cytotoxic drug therapy were systematically evaluated. Relapse-free survival rates increased with the cumulative dosage of CHL and CYC and were higher in children with frequently relapsing than steroid-dependent NS. The fatality rate of the treatment was approximately 1%. Leukopenia occurred in one-third of patients treated with either drug. Severe bacterial infections developed in 1.5% of the patients under CYC and in 6.8% under CHL. Seizures were observed in 3.6% of children treated with CHL. Malignancies were observed in 14 children after high doses of either drug. Females rarely developed permanent gonadal damage. However, no safe threshold for a cumulative amount of CYC was found in males, but there was a marked increase in the risk of oligo- or azoospermia with higher cumulative doses. From this meta-analysis we recommend CYC 2-3 mg/kg body weight for 8-12 weeks as the standard scheme. CHL has higher rates of severe side effects and should be considered a second-line drug.

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Section: Gonadal Toxicitymentioning

confidence: 99%

“…We compiled data from eight studies including 119 patients to investigate the correlation between cumulative dose and sperm count [73,85,89,93,95,99,110,124] (Fig. 3).…”

Section: Gonadal Toxicitymentioning

confidence: 99%

A meta-analysis of cytotoxic treatment for frequently relapsing nephrotic syndrome in children

Latta

Schnakenburg

Ehrich

2001

Pediatric Nephrology

217

145

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“…One of these side effects is gonadal suppression leading to oligospermia or azoospermia (1)(2)(3)(4)(5)(6)(7)(8). Under some conditions azoospermia appears to be permanent and results in sterility.…”

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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“…The patients who had normal testes had also received prolonged treatment with azathioprine (four years). Penso, Lippe, Ehrlich, and Smith (1974) presented a careful follow-up study of seven patients, six of whom were given fairly prolonged (six to 19 months) courses of cyclophosphamide, when aged 11 to 18 years. Five were azoospermic, and four showed no spermatogenesis on testicular biopsy.…”

Section: Gonadal Damage and Teratogenicitymentioning

confidence: 99%

Problems with immunosuppressive agents in renal disease

Cameron¹

1975

J Clin Pathol

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Testicular function in prepubertal and pubertal male patients treated with cyclophosphamide for nephrotic syndrome

Cited by 94 publications

References 25 publications

A meta-analysis of cytotoxic treatment for frequently relapsing nephrotic syndrome in children

A meta-analysis of cytotoxic treatment for frequently relapsing nephrotic syndrome in children

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

Problems with immunosuppressive agents in renal disease

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