title: Anti-Müllerian Hormone Is a Marker for Chemotherapy-Induced Testicular Toxicity.
abstract: Due to increased numbers of young cancer patients and improved survival, the impact of anticancer treatments on fertility has become a major health concern. Despite mounting research on ovarian toxicity, there is paucity of data regarding reliable biomarkers of testicular toxicity. Our aim was to evaluate anti-Müllerian hormone (AMH) as a marker for chemotherapy-induced testicular toxicity. Serum AMH and a panel of gonadal hormones were measured in male cancer patients at baseline and after chemotherapy. In the preclinical setting, mice were injected with diverse chemotherapies and were killed 1 week or 1, 3, or 6 months later. We evaluated spermatogenesis by AMH as well as qualitative and quantitative sperm parameters. Nineteen patients were enrolled, the median age was 38 years (21-44 y). Serum AMH was correlated with increased FSH and T and decreased inhibin-B in gonadotoxic protocols (cisplatin or busulfan) and remained unchanged in nongonadotoxic protocols (capecitabine). AMH expression had the same pattern in mice serum and testes; it was negatively correlated with testicular/epididymal weight and sperm motility. The increase in testicular AMH expression was also correlated with elevated apoptosis (terminal transferase-mediated deoxyuridine 5-triphosphate nick-end labeling) and reduced proliferation (Ki67, proliferating cell nuclear antigen; all seminiferous tubules cells were analyzed). Severely damaged mice testes demonstrated a marked costaining of AMH and GATA-4, a Sertoli cell marker; staining that resembled the pattern of the Sertoli cell-only condition. Our study indicates that the pattern of serum AMH expression, in combination with other hormones, can delineate testicular damage, as determined in both experimental settings. Future large-scale clinical studies are warranted to further define the role of AMH as a biomarker for testicular toxicity.
authors.affiliation: Department of Cell and Developmental Biology (M.L., N.H., R.S.), Sackler Faculty of Medicine, Tel Aviv University, Israel and Institute of Oncology (S.M.S., I.B-A.), Davidoff Center, Rabin Medical Center, Beilinson Campus, Petah-Tiqva 49100, and Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Mattan
authors.initials: M
authors.lastname: Levi
authors.affiliation: Department of Cell and Developmental Biology (M.L., N.H., R.S.), Sackler Faculty of Medicine, Tel Aviv University, Israel and Institute of Oncology (S.M.S., I.B-A.), Davidoff Center, Rabin Medical Center, Beilinson Campus, Petah-Tiqva 49100, and Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Noa
authors.initials: N
authors.lastname: Hasky
authors.affiliation: Department of Cell and Developmental Biology (M.L., N.H., R.S.), Sackler Faculty of Medicine, Tel Aviv University, Israel and Institute of Oncology (S.M.S., I.B-A.), Davidoff Center, Rabin Medical Center, Beilinson Campus, Petah-Tiqva 49100, and Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Salomon M
authors.initials: SM
authors.lastname: Stemmer
authors.affiliation: Department of Cell and Developmental Biology (M.L., N.H., R.S.), Sackler Faculty of Medicine, Tel Aviv University, Israel and Institute of Oncology (S.M.S., I.B-A.), Davidoff Center, Rabin Medical Center, Beilinson Campus, Petah-Tiqva 49100, and Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Shalgi
authors.affiliation: Department of Cell and Developmental Biology (M.L., N.H., R.S.), Sackler Faculty of Medicine, Tel Aviv University, Israel and Institute of Oncology (S.M.S., I.B-A.), Davidoff Center, Rabin Medical Center, Beilinson Campus, Petah-Tiqva 49100, and Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Irit
authors.initials: I
authors.lastname: Ben-Aharon
mesh_terms: D000328:Adult; D000818:Animals; D054304:Anti-Mullerian Hormone / Q000097:blood* / Q000235:genetics / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood* / Q000378:metabolism; D015153:Blotting, Western; D005640:Follicle Stimulating Hormone / Q000096:biosynthesis; D015870:Gene Expression; D006801:Humans; D028322:Inhibin-beta Subunits / Q000097:blood; D008297:Male; D008813:Mice, Inbred ICR; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy; D009929:Organ Size / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013081:Sperm Motility / Q000187:drug effects; D013091:Spermatogenesis / Q000187:drug effects; D013737:Testis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013739:Testosterone / Q000097:blood; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D013739:Testosterone; D054304:Anti-Mullerian Hormone; D005640:Follicle Stimulating Hormone; D028322:Inhibin-beta Subunits