Gonadotropin-Releasing Hormone Analogs for Gonadal Protection During Gonadotoxic Chemotherapy: A Systematic Review and Meta-Analysis

Reprod Sci. 2019 Jul;26(7):939-953. doi: 10.1177/1933719118799203. Epub 2018 Oct 1.


Objective: A systematic review and meta-analysis was conducted to investigate whether gonadotropin-releasing hormone analogs (GnRHa) have a protective role in women treated with alkylating agents.

Data sources: Major databases (PubMED, EMBASE, Cochrane Central Register of Controlled Trials), systematic snowballing, and trial registries were screened from the inception dates until September 2017.

Methods and study selection: Comparative studies involving reproductive-aged women undergoing chemotherapy with or without coadministration of GnRHa were included. Spontaneous menstrual resumption was assessed as a main outcome. Statistical analyses were performed with STATA 14.2 statistical software. Effect estimates were presented as risk ratios (RR) with 95% confidence intervals (CIs).

Results: The literature search yielded 25 436 citations and 84 papers were assessed in full text. Eighteen studies (11 randomized controlled trials [RCTs] and 7 cohort studies) published between 1987 and 2015 were included in the analysis, revealing a significant protective effect of GnRHa (n = 1043; RR:1.38; 95% CI: 1.18-1.63) although with high heterogeneity (I2 = 83.3%). Subgroup analyses revealed a significant benefit of GnRHa cotreatment both in RCTs and in cohort studies. Statistical significance was found in all subgroups by the underlying disease, that is, hematological malignancies, autoimmune diseases, and breast cancer. Sensitivity analyses in GnRH agonist-treated patients, in patients younger than 40 years old, and in patients without supradiaphragmatic radiotherapy also revealed a significant benefit of GnRHa cotreatment.

Conclusion: Our results indicate that concurrent GnRHa administration is an effective method to decrease gonadotoxicity of alkylating agents. The presence of low-quality evidence favoring gonadoprotective effect requires a strong recommendation for offering GnRHa coadministration to young women who are to undergo gonadotoxic chemotherapy.

Capsule: The present systematic review and meta-analysis shows a significant gonadoprotective effect of gonadotropin-releasing hormone analogs in women treated with alkylating agents.

Keywords: alkylating agents; chemotherapy; gonadotropin-releasing hormone analogs; meta-analysis; ovarian protection.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Adolescent
  • Adult
  • Antineoplastic Agents, Alkylating / adverse effects*
  • Cancer Survivors*
  • Female
  • Fertility / drug effects*
  • Fertility Agents, Female / adverse effects
  • Fertility Agents, Female / therapeutic use*
  • Fertility Preservation / methods*
  • Gonadotropin-Releasing Hormone / adverse effects
  • Gonadotropin-Releasing Hormone / analogs & derivatives
  • Gonadotropin-Releasing Hormone / therapeutic use*
  • Humans
  • Infertility, Female / chemically induced
  • Infertility, Female / physiopathology
  • Infertility, Female / prevention & control*
  • Middle Aged
  • Neoplasms / drug therapy*
  • Protective Factors
  • Risk Factors
  • Treatment Outcome
  • Young Adult


  • Antineoplastic Agents, Alkylating
  • Fertility Agents, Female
  • Gonadotropin-Releasing Hormone