title: Ghrelin partially protects against cisplatin-induced male murine gonadal toxicity in a GHSR-1a-dependent manner.
abstract: The chemotherapeutic drug cisplatin causes a number of dose-dependent side effects, including cachexia and testicular damage. Patients receiving a high cumulative dose of cisplatin may develop permanent azoospermia and subsequent infertility. Thus, the development of chemotherapeutic regimens with the optimal postsurvival quality of life (fertility) is of high importance. This study tested the hypothesis that ghrelin administration can prevent or minimize cisplatin-induced testicular damage and cachexia. Ghrelin and its receptor, the growth hormone secretagogue receptor (GHSR-1a), are expressed and function in the testis. Targeted deletion of ghrelin, or its receptor, significantly increases the rate of cell death in the testis, suggesting a protective role. Intraperitoneal administration of vehicle, ghrelin, or cisplatin alone or in combination with ghrelin, in cycles of 9 or 18 days, to adult male C57Bl/6 mice was performed. Body weight was measured daily and testicular and epididymal weight, sperm density and motility, testicular histology, and testicular cell death were analyzed at the time of euthanization. Ghrelin coadministration decreased the severity of cisplatin-induced cachexia and gonadal toxicity. Body, testicular, and epididymal weights significantly increased as testicular cell death decreased with ghrelin coadministration. The widespread damage to the seminiferous epithelium induced by cisplatin administration was less severe in mice simultaneously treated with ghrelin. Furthermore, ghrelin diminished the deleterious effects of cisplatin on testis and body weight homeostasis in wild-type but not Ghsr(-/-) mice, showing that ghrelin's actions are mediated via GHSR. Ghrelin or more stable GHSR agonists potentially offer a novel therapeutic approach to minimize the testicular damage that occurs after gonadotoxin exposure.
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors: Shannon D
authors: SD
authors: Whirledge
authors: Division of Endocrinology, Diabetes, and Metabolism, Michael E. DeBakey Veterans Affairs Medical Center, Baylor College of Medicine, Houston, Texas.
authors: Jose M
authors: JM
authors: Garcia
authors: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, Florida.
authors: Roy G
authors: RG
authors: Smith
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas Scott Department of Urology, Baylor College of Medicine, Houston, Texas Center for Reproductive Medicine, Baylor College of Medicine, Houston, Texas dlamb@bcm.tmc.edu.
authors: Dolores J
authors: DJ
authors: Lamb
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D002100:Cachexia / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control*; D002945:Cisplatin / Q000009:adverse effects* / Q000494:pharmacology*; D054439:Ghrelin / Q000172:deficiency / Q000494:pharmacology / Q000502:physiology*; D006706:Homeostasis / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009929:Organ Size / Q000187:drug effects; D054440:Receptors, Ghrelin / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D013091:Spermatogenesis / Q000187:drug effects; D013094:Spermatozoa / Q000187:drug effects / Q000473:pathology; D013737:Testis / Q000187:drug effects / Q000503:physiopathology*
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D054439:Ghrelin; D054440:Receptors, Ghrelin; C000592182:Ghsr protein, Mouse
keywords: cell death; cisplatin; fertility; ghrelin; spermatogenesis
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