title: Long-Term Follow-Up of Chemotherapy-Induced Ovarian Failure in Young Breast Cancer Patients: The Role of Vascular Toxicity.
abstract: BACKGROUND
  We previously reported that chemotherapy-induced ovarian toxicity may result from acute vascular insult, demonstrated by decreased ovarian blood flow and diminished post-treatment anti-Müllerian hormone (AMH) levels. In the present study, we report the continuous prospective evaluation of ovarian function in that cohort.
  
  
  METHODS
  Patients (aged <43 years) with localized breast cancer were evaluated by transvaginal ultrasound prior to initiation of chemotherapy, immediately at treatment completion, and at 6 and 12 months after treatment cessation. Doppler flow velocity indices of the ovarian vasculature (resistance index [RI], pulsatility index [PI]) were visualized. Hormone markers of ovarian reserve were assessed at the same time points.
  
  
  RESULTS
  Twenty patients were enrolled in the study. Median age was 34 ± 5.24 years. Ovarian blood flow was significantly reduced immediately following chemotherapy (both RI and PI; p = .01). These parameters were partially recovered at later points of assessment (6 and 12 months after treatment); patients aged <35 years significantly regained ovarian blood flow compared with patients aged >35 years (p < .05). AMH dropped dramatically in all patients following treatment (p < .001) and recovered in only 10 patients. Hormone markers of ovarian reserve shortly after chemotherapy depicted a postmenopausal profile for most patients, accompanied by related symptoms. Follicle-stimulating hormone (FSH) levels recovered in 14 of 20 patients and significantly returned to the premenopausal range in patients aged <35 years (p = .04); 10 of 20 resumed menses at 12 months. The pattern of vascular impairment was lessened in patients treated with a trastuzumab-based protocol, although results did not reach statistical significance (p = .068).
  
  
  CONCLUSIONS
  Continuous prospective evaluation of ovarian vasculature and function in a cohort of young patients during and after chemotherapy indicated that ovarian toxicity may derive from acute vascular insult. Age may affect whether patients regain ovarian function, whereas recovery of blood flow and premenopausal FSH levels at later assessment was notable in patients aged <35 years.
  
  
  CONCLUSIONS
  This study explored the role of vascular toxicity in mediating ovarian impairment and recovery following chemotherapy. Continuous prospective evaluation of ovarian vasculature and function in a cohort of young patients during and after chemotherapy indicated that ovarian toxicity may derive from acute vascular insult. Future studies are warranted to further characterize patterns of vascular toxicity of various chemotherapies in clinical practice and to assess the role of chemotherapy-induced vascular toxicity for specific end organs such as the ovary with systemic vascular effect. Elucidating the cause of impairment may facilitate development of measures to minimize vascular toxicity and consequences of acute vascular insult.
authors.affiliation: Institute of Oncology, Davidoff Center, Department of Obstetrics and Gynecology, Helen Schneider Hospital for Women, and Department of Pathology, Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel iritbenaharon@gmail.com iritben@clalit.org.il.
authors.forename: Irit
authors.initials: I
authors.lastname: Ben-Aharon
authors.affiliation: Institute of Oncology, Davidoff Center, Department of Obstetrics and Gynecology, Helen Schneider Hospital for Women, and Department of Pathology, Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Tal
authors.initials: T
authors.lastname: Granot
authors.affiliation: Institute of Oncology, Davidoff Center, Department of Obstetrics and Gynecology, Helen Schneider Hospital for Women, and Department of Pathology, Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Israel
authors.initials: I
authors.lastname: Meizner
authors.affiliation: Institute of Oncology, Davidoff Center, Department of Obstetrics and Gynecology, Helen Schneider Hospital for Women, and Department of Pathology, Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Noa
authors.initials: N
authors.lastname: Hasky
authors.affiliation: Institute of Oncology, Davidoff Center, Department of Obstetrics and Gynecology, Helen Schneider Hospital for Women, and Department of Pathology, Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ana
authors.initials: A
authors.lastname: Tobar
authors.affiliation: Institute of Oncology, Davidoff Center, Department of Obstetrics and Gynecology, Helen Schneider Hospital for Women, and Department of Pathology, Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Shulamith
authors.initials: S
authors.lastname: Rizel
authors.affiliation: Institute of Oncology, Davidoff Center, Department of Obstetrics and Gynecology, Helen Schneider Hospital for Women, and Department of Pathology, Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Rinat
authors.initials: R
authors.lastname: Yerushalmi
authors.affiliation: Institute of Oncology, Davidoff Center, Department of Obstetrics and Gynecology, Helen Schneider Hospital for Women, and Department of Pathology, Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Avi
authors.initials: A
authors.lastname: Ben-Haroush
authors.affiliation: Institute of Oncology, Davidoff Center, Department of Obstetrics and Gynecology, Helen Schneider Hospital for Women, and Department of Pathology, Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Fisch
authors.affiliation: Institute of Oncology, Davidoff Center, Department of Obstetrics and Gynecology, Helen Schneider Hospital for Women, and Department of Pathology, Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Salomon M
authors.initials: SM
authors.lastname: Stemmer
mesh_terms: D000328:Adult; D018943:Anthracyclines / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D015331:Cohort Studies; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D005500:Follow-Up Studies; D006801:Humans; D009367:Neoplasm Staging; D010052:Ovariectomy; D010053:Ovary / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000601:surgery; D016649:Primary Ovarian Insufficiency / Q000097:blood / Q000139:chemically induced* / Q000000981:diagnostic imaging; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects; D000068878:Trastuzumab / Q000008:administration & dosage / Q000009:adverse effects; D014463:Ultrasonography
chemical_list: D018943:Anthracyclines; D043823:Taxoids; D003520:Cyclophosphamide; D005640:Follicle Stimulating Hormone; D000068878:Trastuzumab
keywords: Anti-Müllerian hormone; Chemotherapy; Ovarian toxicity; Vascular toxicity