Impact of route of administration on genotoxic oestrogens concentrations using oral vs transdermal oestradiol in girls with Turner syndrome
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Abstract 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 E2 concentrations 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.
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A randomized controlled trial comparing the metabolic impact of oral E2 versus transdermal E2 found that oral administration resulted in a disproportionate, significant accumulation of genotoxic estrogens compared with transdermal administration.
“A RCT comparing the metabolic impact of oral E2 versus TD E2, found that oral administration resulted in a disproportionate, significant accumulation of genotoxic estrogens compared with TD administration.”
From Clinical practice guidelines for the care of girls and women with Turner syndrome. (2024) · cites this paper as [285]
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- Authors
- Mauras, N., Torres‐Santiago, L., Santen, R., Mericq, V., Ross, J., Colon‐Otero, G., Damaso, L., Hossain, J., Wang, Q., Mesaros, C., & Blair, I. A.
- Affiliations
- Nemours Children's Health System (US)
- University of Virginia (US)
- Division of Endocrinology, Institute of Maternal and Child Research University of Chile Santiago Chile
- Division of Hematology & Oncology Mayo Clinic Jacksonville Florida
- University of Pennsylvania (US)
- Corresponding author
- Mauras, Nelly
- ORCID
- Venue
- Clinical Endocrinology
- Publisher
- Wiley
- Published
- 2018-10-25
- Volume
- 90
- Issue
- 1
- Pages
- 155-161
- ISSN
- 0300-0664 (ISSN-L)
- 1365-2265
- OpenAlex
- W2895048528
- Cited by
- 19
- References
- 36
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 1 · 2022: 4 · 2021: 3 · 2020: 1 · 2019: 3
- FWCI
- 1.07
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- Clinical Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Universidad de Chile (submittedVersion, cc-by-nc-nd)
- Funders
- Genentech Foundation for Biomedical Sciences (NA)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Keywords
- Turner syndrome, estradiol, route of administration, transdermal estradiol, estrone, ovarian failure, breast cancer risk, feminizing hormone therapy, adolescents
- MeSH terms
- Administration, Cutaneous, Administration, Oral, Adolescent, Chromatography, Liquid, Estradiol, Estrogens, Female, Humans, Mutagens, Turner Syndrome, Treatment Outcome, Maximum Tolerated Dose, Tandem Mass Spectrometry
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