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Objective Transdermal, but not oral, estrogen replacement improves bone mineral density (BMD) in athletes with oligoamenorrhea (OA). Our objective was to determine mechanisms that may explain the impact of route of estrogen administration on bone outcomes. Methods Seventy-three participants with OA between 14 and 25 years old received (i) a 17β-estradiol transdermal patch continuously with cyclic oral micronized progesterone (PATCH), (ii) a combined ethinyl estradiol and desogestrel pill (PILL), or (iii) no estrogen/progesterone (NONE) for 12 months. We evaluated morning fasting levels of a marker of bone formation [N-terminal propeptide of type 1 procollagen (P1NP)], a marker of bone resorption (N-telopeptide), IGF-1, insulinlike growth factor binding protein 3, total testosterone, estradiol, SHBG, sclerostin, preadipocyte factor-1 (Pref-1), brain-derived neurotrophic factor (BDNF), calcium, 25(OH) vitamin D, and PTH levels at baseline and 12 months. Results Groups did not differ for age, weight, exercise activity, or markers of bone formation at baseline. Over 12 months, P1NP decreased the most in the PILL group (P = 0.03) associated with a decrease in IGF-1 levels (r = 0.37; P = 0.003). Sclerostin, Pref-1, and BDNF decreased in the PATCH group over 12 months. PATCH had the greatest increases in estradiol (P ≤ 0.0001), and estradiol increases were associated with increases in bone density. Conclusion Transdermal 17β-estradiol given over 12 months does not cause the decrease in IGF-1 observed with oral ethinyl estradiol. It also leads to decreases in sclerostin, Pref-1, and BDNF, which may mediate the beneficial effects of estrogen.

Impact of Route of Estrogen Administration on Bone Turnover Markers in Oligoamenorrheic Athletes and Its Mediators