**Background:** Hormone replacement therapy (HRT) is used to relieve menopausal symptoms, but its use declined after the Women's Health Initiative (WHI) trial in 2002 reported increased risks of myocardial infarction, thromboembolic events, and breast cancer. Transdermal HRT is metabolized differently than oral HRT, with a lower effective dose and reduced serum estrone concentration. This systematic review aimed to summarize available evidence comparing transdermal versus oral estrogen administration for HRT in postmenopausal women, focusing on cardiovascular risk, VTE, lipid metabolism, carbohydrate metabolism, bone mineral density (BMD), and risk of endometrial lesions and breast cancer.
**Methods:** A systematic literature search was conducted in PubMed, clinicaltrials.gov, Scopus, and Web of Science from January 1990 to March 2021. Included studies were randomized controlled trials and observational studies comparing transdermal and oral estrogen administration for HRT in postmenopausal women. Two independent reviewers screened titles and abstracts, and full-text assessment was performed by two other reviewers. Risk of bias was assessed using the Cochrane risk-of-bias tool (Rob 2.0) for RCTs and the Newcastle-Ottawa Scale for observational studies.
**Key Results:** The search identified 1369 manuscripts; after removing 289 duplicates and screening, 76 articles underwent full-text assessment, and 51 studies were included. Most studies were observational and of good quality, while most RCTs had high or medium risk of bias. For cardiovascular risk (6 studies), no route demonstrated significant advantage. For VTE risk (10 studies), oral estrogens were consistently associated with higher risk: Scarabin et al. reported RR 3.5 (95% CI 1.8–6.8) for oral versus RR 0.9 (95% CI 0.5–1.6) for transdermal; Canonico et al. reported OR 4.2 (95% CI 1.5–11.6) for oral versus OR 0.9 (95% CI 0.4–2.1) for transdermal; Sweetland et al. reported RR 1.42 (95% CI 1.22–1.66) for oral versus RR 0.82 (95% CI 0.64–1.06) for transdermal. In women with prothrombotic mutations, oral HRT led to a 25-fold increased VTE risk versus a 4-fold increase with transdermal. For lipid metabolism (12 studies), both routes reduced LDL, but oral increased HDL and triglycerides while transdermal reduced triglycerides. For carbohydrate metabolism (7 studies), both routes reduced insulin resistance; the E3N study reported lower diabetes risk with oral (HR 0.61) versus transdermal (HR 0.78, p=0.031). For BMD (5 studies), both routes increased BMD similarly. For endometrial disease (4 RCTs), no increased risk was found with either route. For breast cancer (7 studies), no significant differences between routes were found; the Million Women Study reported RR 1.32 (1.21–1.45) for oral versus RR 1.24 (1.11–1.39) for transdermal.
**Clinical Implications:** The review provides clear evidence that transdermal HRT is safer than oral HRT regarding VTE risk, which is the strongest clinical difference between the two routes. For other outcomes—BMD, glucose metabolism, lipid profile, breast cancer, endometrial disease, and cardiovascular risk—the routes appear similar. The authors recommend transdermal HRT as the preferred choice, especially in women at increased VTE risk, but emphasize that the choice must be tailored to the individual patient. Further well-designed studies are needed to guide personalized HRT selection.