This randomized controlled trial evaluated the efficacy and safety of various hormone replacement therapy (HRT) regimens in 840 perimenopausal women aged 45-55 years. Participants were allocated to receive either transdermal 17β-estradiol with micronized progesterone, oral conjugated estrogens with medroxyprogesterone acetate, transdermal estradiol with dydrogesterone, or non-hormonal therapy for 24 months. Vasomotor symptom reduction was the main result, with safety profiles, metabolic parameters, and bone density as secondary goals. Results demonstrated that transdermal estradiol with micronized progesterone provided superior symptom relief (82.3% reduction in hot flashes) compared to oral regimens (76.5%) and non-hormonal therapy (42.8%). This combination also showed favorable metabolic effects, including significant improvements in lipid profiles (+8.2 mg/dL HDL, -5.1% LDL) and insulin sensitivity (-18.3% HOMA-IR). Importantly, the transdermal route was associated with significantly lower risks of venous thromboembolism (0.5% vs 1.8% with oral therapy) and excellent endometrial safety. Bone mineral density increased by 2.1% in the transdermal group versus 1.2% loss in controls. The study provides strong evidence that transdermal estradiol with micronized progesterone represents an optimal balance of efficacy and safety for perimenopausal HRT. These findings support early intervention with this regimen in symptomatic women, particularly those with cardiovascular risk factors or concerns about bone health. The comprehensive safety data should help alleviate concerns about HRT risks when initiated during the perimenopausal window of opportunity.
