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

Nelly Mauras, Lournaris Torres-Santiago, Richard Santen, Veronica Mericq, Judith Ross, Gerardo Colon-Otero, Ligeia Damaso, Jobayer Hossain, Qingqing Wang, Clementina Mesaros, Ian A. Blair

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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 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.

Original languageEnglish (US)
JournalClinical Endocrinology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Turner Syndrome
Estradiol
Estrogens
Catechol Estrogens
Quinones
Estrone
Least-Squares Analysis
Estrogen Receptors
Carcinogenesis
Breast
Randomized Controlled Trials
Breast Neoplasms
Liver
Therapeutics

Keywords

  • breast cancer
  • children
  • genotoxic oestrogens
  • LCMSMS assay
  • oestradiol
  • transdermal
  • Turner syndrome

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Impact of route of administration on genotoxic oestrogens concentrations using oral vs transdermal oestradiol in girls with Turner syndrome. / Mauras, Nelly; Torres-Santiago, Lournaris; Santen, Richard; Mericq, Veronica; Ross, Judith; Colon-Otero, Gerardo; Damaso, Ligeia; Hossain, Jobayer; Wang, Qingqing; Mesaros, Clementina; Blair, Ian A.

In: Clinical Endocrinology, 01.01.2018.

Research output: Contribution to journalArticle

Mauras, Nelly ; Torres-Santiago, Lournaris ; Santen, Richard ; Mericq, Veronica ; Ross, Judith ; Colon-Otero, Gerardo ; Damaso, Ligeia ; Hossain, Jobayer ; Wang, Qingqing ; Mesaros, Clementina ; Blair, Ian A. / Impact of route of administration on genotoxic oestrogens concentrations using oral vs transdermal oestradiol in girls with Turner syndrome. In: Clinical Endocrinology. 2018.
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title = "Impact of route of administration on genotoxic oestrogens concentrations using oral vs transdermal oestradiol in girls with Turner syndrome",
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 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.",
keywords = "breast cancer, children, genotoxic oestrogens, LCMSMS assay, oestradiol, transdermal, Turner syndrome",
author = "Nelly Mauras and Lournaris Torres-Santiago and Richard Santen and Veronica Mericq and Judith Ross and Gerardo Colon-Otero and Ligeia Damaso and Jobayer Hossain and Qingqing Wang and Clementina Mesaros and Blair, {Ian A.}",
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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.

PY - 2018/1/1

Y1 - 2018/1/1

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 - breast cancer

KW - children

KW - genotoxic oestrogens

KW - LCMSMS assay

KW - oestradiol

KW - transdermal

KW - Turner syndrome

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