title: Gonadotropin-Releasing Hormone Agonists for Ovarian Function Preservation in Premenopausal Women Undergoing Chemotherapy for Early-Stage Breast Cancer: A Systematic Review and Meta-analysis.
abstract: OBJECTIVE
  Chemotherapy may result in a detrimental effect on ovarian function and fertility in premenopausal women undergoing treatment for early-stage breast cancer (EBC). To minimize risk of harm to ovarian function and fertility for patients in this setting, careful considerations should be made. Gonadotropin-releasing hormone agonists (GnRHa) have been suggested as an alternative to prevent the loss of ovarian function due to exposure to cytotoxic agents, but GnRHa use for ovarian protection in EBC patients is not fully resolved.
  
  
  OBJECTIVE
  To determine the effectiveness of GnRHa administered concurrently with chemotherapy for ovarian function preservation.
  
  
  METHODS
  PubMed, SCOPUS, and Cochrane databases were searched for studies published between January 1975 and March 2015. The abstracts of the American Society of Clinical Oncology Annual Meeting between 1995 and 2014 and the San Antonio Breast Cancer Symposium between 2009 and 2014 were searched as well.
  
  
  METHODS
  Prospective, randomized, clinical trials addressing the role of ovarian suppression with GnRHa in preventing early ovarian dysfunction in premenopausal women undergoing treatment for EBC were selected.
  
  
  METHODS
  Data extraction was performed independently by 2 authors. The methodology and the risk of bias were assessment based on the description of randomization method, withdrawals, and blinding process.
  
  
  METHODS
  Rate of resumption of regular menses after a minimal follow-up period of 6 months following chemotherapy was used as a surrogate to assess the incidence of ovarian dysfunction. Additional secondary outcomes included hormone levels and number of pregnancies. Risk ratio estimates were calculated based on the number of evaluable patients. Analyses were conducted using a random effect model.
  
  
  RESULTS
  Seven studies were included in this analysis, totaling 1047 randomized patients and 856 evaluable patients. The use of GnRHa was associated with a higher rate of recovery of regular menses after 6 months (odds ratio [OR], 2.41; 95% CI, 1.40-4.15; P = .002) and at least 12 months (OR, 1.85; 95% CI, 1.33-2.59; P < .001) following the last chemotherapy cycle. The use of GnRHa was also associated with a higher number of pregnancies (OR, 1.85; 95% CI, 1.02-3.36; P = .04), although this outcome was not uniformly reported and fertility or rate of pregnancy was not the primary outcome in any of the trials.
  
  
  CONCLUSIONS
  Gonadotropin-releasing hormone agonists given with chemotherapy was associated with increased rates of recovery of regular menses in this meta-analysis. Evidence was insufficient to assess outcomes related to GnRHa and ovarian function and fertility and needs further investigation.
authors.affiliation: Hospital Sírio Libanês, São Paulo, Brazil2Instituto do Cancer do Estado de São Paulo, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Rodrigo R
authors.initials: RR
authors.lastname: Munhoz
authors.affiliation: Hospital Sírio Libanês, São Paulo, Brazil2Instituto do Cancer do Estado de São Paulo, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Allan A L
authors.initials: AA
authors.lastname: Pereira
authors.affiliation: Universidade Estadual de Campinas, Campinas, Brazil.
authors.forename: André D
authors.initials: AD
authors.lastname: Sasse
authors.affiliation: Hospital Sírio Libanês, São Paulo, Brazil2Instituto do Cancer do Estado de São Paulo, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Paulo M
authors.initials: PM
authors.lastname: Hoff
authors.affiliation: Breast Cancer Service, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Traina
authors.affiliation: Breast Cancer Service, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Hudis
authors.affiliation: Hospital HCor/Oncoclínicas, São Paulo, Brazil.
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Marques
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D016009:Chi-Square Distribution; D005260:Female; D005298:Fertility / Q000187:drug effects*; D005300:Fertility Agents, Female / Q000009:adverse effects / Q000627:therapeutic use*; D059247:Fertility Preservation / Q000379:methods*; D006801:Humans; D007247:Infertility, Female / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D008598:Menstruation / Q000187:drug effects; D008875:Middle Aged; D009367:Neoplasm Staging; D016017:Odds Ratio; D010053:Ovary / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D011247:Pregnancy; D018873:Pregnancy Rate; D017697:Premenopause; D011966:Receptors, LHRH / Q000819:agonists* / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D005300:Fertility Agents, Female; D011966:Receptors, LHRH