Gonadotropin-releasing hormone (GnRH) analogues for premenstrual syndrome (PMS).
Level 1 - systematic review of randomized trials
Systematic review and meta-analysis of randomized controlled trials
PubMed 40492482 · doi:10.1002/14651858.CD011330.pub2
What was done
This Cochrane systematic review and meta-analysis evaluated randomized controlled trials (RCTs) of GnRH analogues (agonists or antagonists), with or without add-back therapy (estrogen, progestogen, or tibolone), for premenstrual syndrome (PMS/PMDD) in women of reproductive age diagnosed over at least two prospective cycles without current psychiatric disorders. Comparators included placebo, no treatment, another GnRH regimen, or add-back. Primary outcomes included overall PMS symptom severity, quality of life, and adverse events.
What was found
Eleven RCTs (275 women) were included; none assessed GnRH antagonists. - GnRH agonists without add-back versus placebo: Improved global symptoms (SMD -1.23, 95% CI -1.76 to -0.71; 9 RCTs, 173 women; high-certainty evidence), but increased withdrawal due to adverse events (RR 4.24, 95% CI 1.10 to 16.36; 6 RCTs, 140 women; high-certainty evidence) and menopausal side effects (RR 1.93, 95% CI 0.83 to 4.48; 2 RCTs, 23 women; low-certainty evidence). - GnRH agonists with add-back versus placebo: May improve global symptoms (MD -3.89, 95% CI -6.19 to -1.59; 1 RCT, 31 women; low certainty); effect on adverse-event withdrawals was uncertain (RR 2.86, 95% CI 0.12 to 66.44; 1 RCT, 41 women; very low certainty). - Add-back during GnRH agonist therapy: Tibolone add-back showed uncertain effects on symptoms (SMD -0.37, 95% CI -0.11 to 0.38; 1 RCT, 28 women; very low certainty). Estrogen plus cyclical progestogen add-back worsened global symptoms compared to placebo add-back (SMD 0.90, 95% CI 0.17 to 1.63; 1 RCT, 32 women; low certainty). Low-dose versus standard-dose add-back was inconclusive (MD -11.90, 95% CI -28.51 to 4.71; 1 RCT, 15 women; low certainty).
Why it matters
GnRH agonists provide strong symptom relief in PMS by inducing anovulation, but severe hypoestrogenic side effects and high withdrawal rates limit standalone use. High-quality evidence is currently lacking to establish whether add-back regimens can mitigate menopausal side effects without compromising therapeutic efficacy.
Limits
The total sample size across all 11 trials was small (275 women). No studies evaluated GnRH antagonists. Quality of life and long-term effects on bone health were not reported, and reporting on specific adverse events was incomplete. Included trials frequently suffered from serious imprecision and high risk of bias relating to blinding and attrition, with high statistical heterogeneity (I² = 72%) in the primary comparison.
Cited by
- supports The drop in both estrogen and progesterone prior to menstruation triggers premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) symptoms, including breast tenderness, irritability, and emotional distress.