To evaluate the effects of physiological dose 17 beta-estradiol (E2) replacement on low bone mineral density (BMD) and compare the results of oral and transdermal (TD) E2 administration in adolescents and young women with hypogonadism DESIGN, SETTING, AND PARTICIPANTS: We retrospectively reviewed the medical records of patients aged 15 to 24 years who were diagnosed with hypogonadism, who had begun receiving oral or TD E2 replacement, and whose initial dual-energy X-ray absorptiometry scan detected a lumbar spine BMD Z-score of -1 or lower between 2014 and 2018. The patients were divided into 2 groups according to the E2 route of administration as those who received 2 mg orally (Group 1) and 0.1 mg TD (Group 2). None MAIN OUTCOME MEASURE: BMD scans of the patients at baseline and repeated within 2 years after E2 replacement RESULTS: In total, 43 patients who met the inclusion criteria were included in the study. Two groups did not differ for BMD scores at baseline. A significant improvement in BMD was observed with physiological dose E2 replacement in both groups. Mean BMD Z-score increased by +0.7 (95% CI, 0.47-0.93) in response to TD E2 administration, compared with +0.41 (95% CI, 0.25-0.58) during oral E2 replacement (P=.037). We conclude that physiological dose E2 replacement, even within a short period of 2 years, has a significant beneficial effect on bone mass acquisition on the lumbar spine. Our study also demonstrates the possible superiority of TD E2 replacement over the oral route in increasing lumbar spine BMD.