Randomized trial of aromatase inhibitors, growth hormone, or combination in pubertal boys with idiopathic, short stature

Context: Growth of short children in puberty is limited by the effect of estrogen on epiphyseal fusion. Objectives: To compare: 1) the efficacy and safety of aromatase inhibitors (AIs) vs GH vs AI/GH on increasing adult height potential in pubertal boys with severe idiopathic short stature (ISS); and 2) differences in body composition among groups. Design: Randomized three-arm open-label comparator. Setting: Outpatient clinical research. Patients: Seventy-six pubertal boys [mean (SE) age, 14.1 (0.1) years] with ISS [height SD score (SDS), -2.3 (0.0)]. Intervention: Daily AIs (anastrozole or letrozole), GH, or AI/GH for 24-36 months. Outcomes: Anthropometry, bone ages, dual x-ray absorptiometry, spine x-rays, hormones, safety labs. Results: Height gain [mean (SE)] at 24 months was: AI, +14.0 (0.8) cm; GH, +17.1 (0.9) cm; AI/GH, + 18.9 (0.8) cm(P < .0006, analysis of covariance). Height SDS was: AI, -1.73 (0.12); GH, -1.43 (0.14); AI/GH, -1.25 (0.12) (P < .0012). Those treated through 36 months grew more. Regardless of treatment duration, height SDS at near-final height [n = 71; age, 17.4 (0.2) years; bone age, 15.3 (0.1) years; height achieved, similar to 97.6%] was: AI, -1.4 (0.1); GH, -1.4 (0.2); AI/GH, -1.0 (0.1) (P = .06). Absolute height change was: AI, +18.2 (1.6) cm; GH, +20.6 (1.5) cm; AI/GH, + 22.5 (1.4) cm (P = .01) (expected height gain at -2.0 height SDS, +13.0 cm). AI/GH had higher fat free mass accrual. Measures of bone health, safety labs, and adverse events were similar in all groups. Letrozole caused higher T and lower estradiol than anastrozole. Conclusions: Combination therapy with AI/GH increases height potential in pubertal boys with ISS more thanGHand AI alone treated for 24-36 months with a strong safety profile.Thrasher Research Fund National Institutes of Health from the National Center for Advancing Translational Sciences UL1TR00013

Impact of route of administration on genotoxic oestrogens concentrations using oral vs transdermal oestradiol in girls with Turner syndrome

© 2018 John Wiley & Sons Ltd Objective: The established link between oestrogen and breast cancer occurs via both oestrogen receptor (ER)-mediated and non ER-mediated mechanisms. The term genotoxic estrogens describes mutagenic metabolites, including oestrogen catechols and quinones, which have been linked to breast carcinogenesis in post-menopausal women. We aimed to assess whether the route of administration of 17β oestradiol (E 2 ) affects the accumulation of genotoxic oestrogen metabolites in a model of ovarian failure in young girls with Turner syndrome. Methods: Stored plasma samples obtained at 0 and 12 months were used from 40 adolescents with Turner syndrome who participated in a 12 months randomized controlled trial of the metabolic impact of E 2 orally (2 mg/d) vs transdermally (100 µg/d); dose escalation allowed matching of unconjugated E 2 levels in the parent study. We measured 12 oestrogen metabolites (total concentrations = conjugated and unconjugated) using a highly se