title: Effect of letrozole on moderate and severe early-onset ovarian hyperstimulation syndrome in high-risk women: a prospective randomized trial.
abstract: BACKGROUND
  Ovarian hyperstimulation syndrome is an iatrogenic complication of controlled ovarian stimulation. Early ovarian hyperstimulation syndrome occurs during luteal phase of controlled ovarian stimulation within 9 days after human chorionic gonadotropin trigger and reflects an acute consequence of this hormone on the ovaries. Late ovarian hyperstimulation syndrome occurs 10 or more days after human chorionic gonadotropin trigger and reflects increased endogenous human chorionic gonadotropin levels following pregnancy. Human chorionic gonadotropin stimulates granulosa-lutein cells to produce vascular endothelial growth factor messenger RNAs, which in turn raises serum vascular endothelial growth factor concentration and increases vascular permeability in women with ovarian hyperstimulation syndrome. Efforts to reduce the incidence and severity of ovarian hyperstimulation syndrome after oocyte retrieval, and in particular primary prevention efforts, are vital to prevent thrombogenesis and other serious complications.
  
  
  OBJECTIVE
  The objective of the study was to compare the efficacy of letrozole, an aromatase inhibitor, with aspirin in primary prevention of early ovarian hyperstimulation syndrome and to compare vascular endothelial growth factor levels between groups.
  
  
  METHODS
  Participants in this prospective randomized trial included 238 participants undergoing cryopreservation of the whole embryos after oocyte retrieval with at least 1 of the following high-risk factors for ovarian hyperstimulation syndrome: oocyte retrieval ≥25; estradiol level ≥5000 pg/mL on the day of human chorionic gonadotropin administration; and clinical or ultrasonographic evidence of ovarian hyperstimulation syndrome on the day of oocyte retrieval, such as ultrasonographic evidence of ascites. After human chorionic gonadotropin triggering, experimental (119 cases) and control (119 cases) groups received letrozole and aspirin, respectively, for 5 days. The 5 categories of ovarian hyperstimulation syndrome include no, yes-mild, yes-moderate, yes-severe, and yes-critical. The primary outcome was the incidence and severity of early ovarian hyperstimulation syndrome. The secondary outcome included vascular endothelial growth factor level both on the second and seventh day after the human chorionic gonadotropin trigger, and clinical and laboratory features of ovarian hyperstimulation syndrome symptoms.
  
  
  RESULTS
  The incidence of ovarian hyperstimulation syndrome was significantly higher in women receiving aspirin, compared with letrozole (90.2% vs 80.4%, P = .044). Moderate and severe ovarian hyperstimulation syndrome was also higher in the aspirin group, 45.1%, compared with the letrozole group, 25.0% (P = .002). Moreover, the duration of luteal phase was shortened in letrozole group compared with aspirin group (8.1 ± 1.1 days vs 10.5 ± 1.9 days, P < .001). The vascular endothelial growth factor level was significantly higher in the letrozole-treated group than aspirin-treated group (0.49 ± 0.26 vs 0.42 ± 0.22, P = .029).
  
  
  CONCLUSIONS
  Letrozole was more effective than aspirin in decreasing the incidence of moderate and severe early-onset ovarian hyperstimulation syndrome. Our results indicate that ovarian hyperstimulation syndrome might be caused through a luteolytic effect rather than through modulation of vascular endothelial growth factor, racing by a decline in estradiol and termination of early-onset ovarian hyperstimulation syndrome in advance in high-risk women with cryopreservation of the whole embryos.
authors.affiliation: Center for Reproductive Medicine and Department of Gynecology and Obstetrics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Qingyun
authors.initials: Q
authors.lastname: Mai
authors.affiliation: Center for Reproductive Medicine and Department of Gynecology and Obstetrics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Obstetrics and Gynecology, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Center for Reproductive Medicine and Department of Gynecology and Obstetrics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Yingyi
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Center for Reproductive Medicine and Department of Gynecology and Obstetrics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Kejun
authors.initials: K
authors.lastname: Huang
authors.affiliation: Center for Reproductive Medicine and Department of Gynecology and Obstetrics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Center for Reproductive Medicine and Department of Gynecology and Obstetrics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: zhoucanquan@hotmail.com.
authors.forename: Canquan
authors.initials: C
authors.lastname: Zhou
mesh_terms: D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D001201:Ascites / Q000000981:diagnostic imaging / Q000209:etiology; D001241:Aspirin / Q000627:therapeutic use; D006063:Chorionic Gonadotropin / Q000627:therapeutic use; D004958:Estradiol / Q000378:metabolism; D005260:Female; D006801:Humans; D000077289:Letrozole; D008183:Luteal Phase; D009570:Nitriles / Q000627:therapeutic use*; D054315:Oocyte Retrieval / Q000379:methods; D016471:Ovarian Hyperstimulation Syndrome / Q000150:complications / Q000000981:diagnostic imaging / Q000378:metabolism / Q000517:prevention & control*; D010062:Ovulation Induction / Q000379:methods; D011322:Primary Prevention; D012102:Reproductive Control Agents / Q000627:therapeutic use; D018570:Risk Assessment; D012720:Severity of Illness Index; D014230:Triazoles / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D047072:Aromatase Inhibitors; D006063:Chorionic Gonadotropin; D009570:Nitriles; D012102:Reproductive Control Agents; D014230:Triazoles; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D004958:Estradiol; D000077289:Letrozole; D001241:Aspirin
keywords: aspirin; in vitro fertilization; letrozole; ovarian hyperstimulation syndrome; vascular endothelial growth factor