Subcutaneous Estradiol Pellets as Hormone Therapy in Menopause: Clinical Pharmacology, Patient Selection and Safety Considerations

<b>Background:</b> Among hormone therapy options for menopause, subcutaneous estradiol pellets offer sustained hormone release, avoid first-pass hepatic metabolism, and maintain a near-physiological estradiol-to-estrone ratio. Despite clinical use since the 1940s, standardized protocols remain lacking. <b>Methods:</b> We performed a critical narrative review following SANRA criteria. PubMed, Scopus, Embase, and LILACS were searched from 1949 to 2024 for randomized trials, cohort studies, and case series on estradiol pellets and outcomes in symptom control, bone health, pharmacokinetics, and safety. Animal studies, editorials, and reports without primary clinical data were excluded. <b>Results:</b> Following an initial peak within the first week, pellets maintain stable serum estradiol levels within the early-to-mid follicular range (50-113 pg/mL depending on dose) for four to six months, with a near-physiological E2:E1 ratio of approximately 1.5:1. The 25 mg dose achieves mean levels of 50-70 pg/mL, effectively controls vasomotor symptoms, and increases bone mineral density. Compared with oral estradiol, pellets bypass hepatic first-pass metabolism, resulting in neutral or favorable metabolic and thrombotic profiles. Compared with transdermal therapy, pellets provide more predictable pharmacokinetics, especially in women with low skin absorption. Safety concerns, including bleeding, tachyphylaxis, and supraphysiological levels, are mainly associated with excessive dosing, premature reimplantation, or lack of endometrial protection in women with a uterus. <b>Conclusions:</b> Estradiol pellets are an effective option for women with poor transdermal absorption, low adherence to daily regimens, or surgical menopause. Safety depends on clinical management with individualized dosing, adequate endometrial protection, and laboratory monitoring. Long-term comparative studies are needed to standardize protocols and support broader evidence-based use.