Comparative Efficacy and Safety of Modern Treatment Modalities for Genitourinary Syndrome of Menopause: A Systematic Review and Network Meta‐Analysis

Background Genitourinary syndrome of menopause (GSM) is a chronic consequence of hypoestrogenism affecting vaginal, sexual and lower urinary tract health. Treatments include local vaginal oestrogen, intravaginal prasterone, oral ospemifene, hyaluronic acid preparations, moisturisers/lubricants and energy‐based interventions, but comparative evidence is heterogeneous. Objectives To compare the relative efficacy and safety of contemporary GSM therapies using a systematic review and class‐level network meta‐analysis (NMA) of randomised controlled trials. Search Strategy MEDLINE/PubMed, Scopus, Cochrane CENTRAL, Web of Science, Google Scholar, ClinicalTrials.gov and WHO ICTRP were searched from inception to March 2026, with backward and forward citation searching. Selection Criteria Randomised controlled trials enrolling postmenopausal women with symptomatic GSM or equivalent diagnoses. Data Collection and Analysis Two reviewers independently screened, extracted and linked reports from the same trial family and assessed RoB 2. The primary outcome was harmonised patient‐reported symptom burden, using a prespecified hierarchy of global symptom score, most bothersome symptom, dyspareunia and vaginal dryness. A frequentist random‐effects consistency NMA generated; Hedges g standardised mean differences (SMDs), 95% confidence intervals (CIs), prediction intervals and P‐scores. Heterogeneity was estimated by REML; node splitting, a design‐by‐treatment interaction decomposition and sensitivity analyses assessed incoherence and influence. Confidence in all 21 network comparisons was evaluated with CINeMA using a validated percentage contribution matrix. Results Twenty‐six efficacy publications represented 24 unique trial families and 4958 randomised participants after denominator adjudication. The primary symptom NMA included 15 trial families, seven nodes and 3415 participants. Versus placebo/sham/control, local vaginal oestrogen was the only class with a CI excluding the null (SMD 0.34, 95% CI 0.02–0.66). Estimates were imprecise for prasterone (0.37, −0.10 to 0.84), hyaluronic acid (0.31, −0.10 to 0.72), ospemifene (0.24, −0.38 to 0.87), moisturiser/lubricant (0.15, −0.37 to 0.67) and CO 2 laser (0.03, −0.56 to 0.61). Heterogeneity remained material ( τ 2 = 0.097; I 2 = 65.6%). Node splitting showed no statistically detectable local incoherence (all p ≥ 0.35) and the global design‐by‐treatment interaction decomposition was also non‐significant (Q = 4.90, df = 3, p = 0.179). P‐scores were similar for local oestrogen (0.704) and prasterone (0.704) and rankings were sensitivity‐dependent. CINeMA confidence was low for local oestrogen versus placebo/sham/control and prasterone versus placebo/sham/control and very low for the remaining 19 network comparisons. Radiofrequency was not included in the primary symptom NMA because a hierarchy‐compatible continuous symptom effect with extractable dispersion was unavailable. Overall RoB 2 was low for 2 trial families, some concerns for 11 and high for 11. Conclusions Local vaginal oestrogen remains the best‐supported benchmark for symptomatic GSM. Hyaluronic acid, prasterone and ospemifene have clinically relevant evidence, but cross‐class estimates are imprecise and rankings are unstable. CO 2 laser and radiofrequency should not be positioned as equivalent or superior first‐line treatments on the available evidence. The data support individualised stepped care rather than a definitive treatment hierarchy.