Efficacy and safety of pulsatile gonadotropin-releasing hormone therapy among patients with idiopathic and functional hypothalamic amenorrhea: a systematic review of the literature and a meta-analysis

Fertil Steril. 2018 Apr;109(4):708-719.e8. doi: 10.1016/j.fertnstert.2017.12.028. Epub 2018 Mar 28.


Objective: To systematically review and appraise the existing evidence in relation to the efficacy and safety of pulsatile gonadotropin-releasing hormone (pGnRH) for the treatment of women with hypothalamic amenorrhea (HA).

Design: Systematic review and meta-analysis.

Setting: Not applicable.

Patient(s): A total of 35 studies (three randomized and 32 observational) encompassing 1,002 women with HA.

Intervention(s): None.

Main outcome measure(s): Primary outcomes: ovulation rate (OvR), pregnancy per ovulatory cycle rate (POR), and live birth per ovulatory cycle rate (LBOR).

Secondary outcomes: multiple gestation (MG), ovarian hyperstimulation syndrome (OHSS), and superficial thrombophlebitis (ST) rates. The summary measures were expressed as proportions and 95% confidence intervals (CI).

Result(s): Pulsatile GnRH treatment appears to achieve high OvRs. A trend toward high PORs and LBORs among women with HA is demonstrated. SC pGnRH achieves comparable OvR compared with IV pGnRH. The incidence of OHSS is low and of mild severity. Treatment with pGnRH is associated with low but slightly higher MG rates compared with the general population. IV administered pGnRH is rarely associated with ST.

Conclusion(s): The high OvRs leading to a high rate of singleton pregnancies and the low likelihood of OHSS render the pGnRH treatment modality both effective and safe for the treatment of women with HA of either primary or secondary origin.

Keywords: Hypothalamic amenorrhea; infertility; meta-analysis; pulsatile GnRH.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Adolescent
  • Adult
  • Amenorrhea / complications
  • Amenorrhea / diagnosis
  • Amenorrhea / drug therapy*
  • Amenorrhea / physiopathology
  • Female
  • Fertility Agents, Female / administration & dosage*
  • Fertility Agents, Female / adverse effects
  • Gonadotropin-Releasing Hormone / administration & dosage*
  • Gonadotropin-Releasing Hormone / adverse effects
  • Humans
  • Hypothalamus / physiopathology*
  • Infertility, Female / diagnosis
  • Infertility, Female / drug therapy*
  • Infertility, Female / etiology
  • Infertility, Female / physiopathology
  • Live Birth
  • Ovulation / drug effects*
  • Ovulation Induction / adverse effects
  • Ovulation Induction / methods*
  • Pregnancy
  • Pregnancy Rate
  • Pulse Therapy, Drug
  • Risk Assessment
  • Risk Factors
  • Treatment Outcome
  • Young Adult


  • Fertility Agents, Female
  • Gonadotropin-Releasing Hormone