TY - JOUR
T1 - Impact of route of administration on genotoxic oestrogens concentrations using oral vs transdermal oestradiol in girls with Turner syndrome
AU - Mauras, Nelly
AU - Torres-Santiago, Lournaris
AU - Santen, Richard
AU - Mericq, Veronica
AU - Ross, Judith
AU - Colon-Otero, Gerardo
AU - Damaso, Ligeia
AU - Hossain, Jobayer
AU - Wang, Qingqing
AU - Mesaros, Clementina
AU - Blair, Ian A.
N1 - Funding Information:
The authors are grateful to the Genentech Center for Clinical Research in Endocrinology for the funding of the studies that generated the study samples and to the Nemours Research Programs. The authors grateful to Shawn Sweeten for technical support of Nemours biomedical laboratory; to Sylvia Kyle, librarian and to all the patients, volunteers and their families for participating in these studies.
Funding Information:
Dr Mauras reports grants from Genentech, non‐financial support from Novartis, during the conduct of the study; grants and personal fees from Opko, grants from Orphan, outside the submitted work; Dr Colon‐Otero reports grants from Novartis, outside the submitted work; Dr Mericq reports personal fees from Novo Nordisk, Novartis and Merck, outside the submitted work; Dr Ross reports personal fees from Opko, grants and personal fees from NovoNordisk, out‐ side the submitted work; Dr Santen reports personal fees from Therapeutics MD, personal fees from Sermonix Incorporated, grants from Panterhei Oncology Inc, outside the submitted work. All other authors have nothing to disclose.
Publisher Copyright:
© 2018 John Wiley & Sons Ltd
PY - 2019/1
Y1 - 2019/1
N2 - 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 (E2) 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 E2 orally (2 mg/d) vs transdermally (100 µg/d); dose escalation allowed matching of unconjugated E2 levels in the parent study. We measured 12 oestrogen metabolites (total concentrations = conjugated and unconjugated) using a highly sensitive LCMSMS assay. Results from 48 normally menstruating adolescents were used for comparison. Results: After treatment, least square mean (SE) total E2concentrations were higher in the oral vs transdermal group (6784 pmol/L vs 1123 [1614], P < 0.0001), as was oestrone (E1) (91 060 pmol/L vs 19 278 [16 534], P < 0.0001). Also, higher after oral treatment were catechol-oestrogens 4-hydroxy-E2 (149 vs 28 [±49] pmol/L), 2-hydroxy-E2 (300 vs 76 [±52]), 4-hydroxy-E1(450 vs 105 [±113]), 2-hydroxy-E1(3094 vs 740 [±684]) and 16α-hydroxy-E1 (3,007 vs 157 [±534]) (<0.001 between groups). Levels were much closer to controls in the transdermal group. Conclusions: Common feminizing doses of oral oestradiol for 12 months result in substantial accumulation of unphysiologic, genotoxic oestrogens compared to transdermal oestradiol, expanding concerns about oral oestrogens’ first hepatic passage. Further studies assessing long-term risks of these metabolites in women taking different forms of oestrogen are needed.
AB - 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 (E2) 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 E2 orally (2 mg/d) vs transdermally (100 µg/d); dose escalation allowed matching of unconjugated E2 levels in the parent study. We measured 12 oestrogen metabolites (total concentrations = conjugated and unconjugated) using a highly sensitive LCMSMS assay. Results from 48 normally menstruating adolescents were used for comparison. Results: After treatment, least square mean (SE) total E2concentrations were higher in the oral vs transdermal group (6784 pmol/L vs 1123 [1614], P < 0.0001), as was oestrone (E1) (91 060 pmol/L vs 19 278 [16 534], P < 0.0001). Also, higher after oral treatment were catechol-oestrogens 4-hydroxy-E2 (149 vs 28 [±49] pmol/L), 2-hydroxy-E2 (300 vs 76 [±52]), 4-hydroxy-E1(450 vs 105 [±113]), 2-hydroxy-E1(3094 vs 740 [±684]) and 16α-hydroxy-E1 (3,007 vs 157 [±534]) (<0.001 between groups). Levels were much closer to controls in the transdermal group. Conclusions: Common feminizing doses of oral oestradiol for 12 months result in substantial accumulation of unphysiologic, genotoxic oestrogens compared to transdermal oestradiol, expanding concerns about oral oestrogens’ first hepatic passage. Further studies assessing long-term risks of these metabolites in women taking different forms of oestrogen are needed.
KW - LCMSMS assay
KW - Turner syndrome
KW - breast cancer
KW - children
KW - genotoxic oestrogens
KW - oestradiol
KW - transdermal
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U2 - 10.1111/cen.13869
DO - 10.1111/cen.13869
M3 - Article
C2 - 30281805
AN - SCOPUS:85055568114
SN - 0300-0664
VL - 90
SP - 155
EP - 161
JO - Clinical Endocrinology
JF - Clinical Endocrinology
IS - 1
ER -