Original article| Volume 23, ISSUE 1, P84-90, January 2023

Measurable Serum Estradiol and Estrone in Women 36-56 Years During Adjuvant Treatment With Aromatase Inhibitors for a Hormone Receptor-Positive Breast Cancer. Case Studies and Cross-sectional Study Using an Ultra-sensitive LC-MS/MS-Method.

Published:September 27, 2022DOI:


      • Estrone might be a better marker then estradiol to detect ovarian reactivation.
      • Breast cancer patients aged 36 to 56 years need to be monitored closely during adjuvant treatment with aromatase inhibitors


      Background and Purpose

      Ovarian function recovery (OFR) during adjuvant use of an aromatase inhibitor (AI) negatively impacts breast cancer outcome. We measured serum FSH and estrogen levels in consecutive AI-users with an uncertain menopausal status during follow-up and report associated risk factors of OFR


      A retrospective cross sectional observational monocentric study including breast cancer patients in follow-up using an adjuvant AI, age 36 to 56 years, with at least one serum estradiol (E2) and estrone (E1) measurement between 2013 and 2020. Estrogens were quantified using a sensitive liquid chromatography-tandem mass spectrometry method (LC-MS/MS). Women on LHRH agonist were included while those with a bilateral oophorectomy or ovarian irradiation were not. We aimed to identify risk factors of OFR considering age, body mass index (BMI), previous chemotherapy and duration of AI use. Univariable analysis was used to evaluate risk factors of OFR.


      E2/E1 levels were assessed in 207 patients with a median age of 50 years (range 36-56). 17 of 159 on AI (10.7%) and 3 of 48 on AI + LHRH (6.3%) had OFR. Seven out of 17 patients (41,2%) with OFR in the AI only group and 2 out of 3 patients (66,7%) in the AI+LHRH agonist group were in amenorrhea. Age <50 y and adjuvant chemotherapy were statistically significantly different between the OFR group and the group with postmenopausal estrogen levels.


      Breast cancer patients aged 36 to56 years need to be monitored closely during adjuvant treatment with aromatase inhibitors: to confirm menopausal status, to evaluate compliance and to ensure ovarian activity remains adequately suppressed. Estrone might be a better marker then estradiol to detect ovarian reactivation.



      OFR (Ovarian function recovery), OFS (Ovarian function suppression), LHRH (luteinizing hormone-releasing hormone), TES (total estrogen suppression), LC-MS/MS (liquid chromatography-tandem mass spectrometry), CIA (chemotherapy induced amenorrhea), LLOQ (lower limit of quantification)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Clinical Breast Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Rydén L
        • Heibert Arnlind M
        • Vitols S
        • Höistad M
        • Ahlgren J
        Aromatase inhibitors alone or sequentially combined with tamoxifen in postmenopausal early breast cancer compared with tamoxifen or placebo - Meta-analyses on efficacy and adverse events based on randomized clinical trials.
        Breast. 2016; 26: 106-114
        • Howell A
        • Cuzick J
        • Baum M
        • et al.
        Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer.
        Lancet. 2005; 365: 60-62
        • Cuzick J
        • Sestak I
        • Baum M
        • et al.
        Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial.
        Lancet Oncol. 2010; 11: 1135-1141
        • Schneider R
        • Barakat A
        • Pippen J
        • Osborne C.
        Aromatase inhibitors in the treatment of breast cancer in post-menopausal female patients: an update.
        Breast Cancer (Dove Med Press). 2011; 3: 113-125
        • Jakesz R
        • Jonat W
        • Gnant M
        • et al.
        Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial.
        Lancet. 2005; 366: 455-462
        • Dowsett M
        • Cuzick J
        • Ingle J
        • et al.
        Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen.
        J Clin Oncol. 2010; 28: 509-518
        • Guerrero A
        • Gavilá J
        • Folkerd E
        • et al.
        Incidence and predictors of ovarian function recovery (OFR) in breast cancer (BC) patients with chemotherapy-induced amenorrhea (CIA) who switched from tamoxifen to exemestane.
        Ann Oncol. 2013; 24: 674-679
        • Smith IE
        • Dowsett M
        • Yap YS
        • et al.
        Adjuvant aromatase inhibitors for early breast cancer after chemotherapy-induced amenorrhoea: caution and suggested guidelines.
        J Clin Oncol. 2006; 24: 2444-2447
        • Henry NL
        • Xia R
        • Banerjee M
        • et al.
        Predictors of recovery of ovarian function during aromatase inhibitor therapy.
        Ann Oncol. 2013; 24: 2011-2016
        • Krekow LK
        • Hellerstedt BA
        • Collea RP
        • et al.
        Incidence and predictive factors for recovery of ovarian function in amenorrheic women in their 40s treated with letrozole.
        J Clin Oncol. 2016; 34: 1594-1600
        • van Hellemond IEG
        • Vriens IJH
        • Peer PGM
        • et al.
        • on behalf of the Dutch Breast Cancer Research Group (BOOG),
        Ovarian function recovery during anastrozole in breast cancer patients with chemotherapy-induced ovarian function failure.
        J Natl Cancer Inst. 2017; 109
        • Pauwels S
        • Antonio L
        • Jans I
        • et al.
        Sensitive routine liquid chromatography-tandem mass spectrometry method for serum estradiol and estrone without derivatization.
        Anal Bioanal Chem. 2013; 405: 8569-8577
        • Han SN
        • Van Peer S
        • Peccatori F
        • Gziri MM
        • Amant F
        International network on cancer IfaP. Contraception is as important as fertility preservation in young women with cancer.
        Lancet. 2015; 385: 508
        • van Hellemond IEG
        • Vriens IJH
        • Peer PGM
        • et al.
        Efficacy of anastrozole after tamoxifen in early breast cancer patients with chemotherapy-induced ovarian function failure.
        Int J Cancer. 2019; 145: 274-283
        • Kim HA
        • Lee JW
        • Nam SJ
        • et al.
        Adding ovarian suppression to tamoxifen for premenopausal breast cancer: a randomized phase III trial.
        J Clin Oncol. 2020; 38: 434-443
        • Francis PA
        • Pagani O
        • Fleming GF
        • et al.
        Tailoring adjuvant endocrine therapy for premenopausal breast cancer.
        N Engl J Med. 2018; 379: 122-137
        • Pagani O
        • Regan MM
        • Walley BA
        • et al.
        Adjuvant exemestane with ovarian suppression in premenopausal breast cancer.
        N Engl J Med. 2014; 371: 107-118
        • Bellet M
        • Gray KP
        • Francis PA
        • et al.
        Twelve-month estrogen levels in premenopausal women with hormone receptor-positive breast cancer receiving adjuvant triptorelin plus exemestane or tamoxifen in the suppression of ovarian function trial (SOFT): the SOFT-EST substudy.
        J Clin Oncol. 2016; 34: 1584-1593
        • Paluch-Shimon S
        • Cardoso F
        • Partridge AH
        • et al.
        ESO-ESMO 4th international consensus guidelines for breast cancer in young women (BCY4).
        Ann Oncol. 2020; 31: 674-696
        • GradisharWJ A
        • AbrahamJ AftR
        • AgneseD Alli- son KH
        • et al.
        NCCN guidelines version 5.
        Invasive Breast Cancer. 2020; 67: 67
        • Folkerd EJ
        • Lønning PE
        • Dowsett M.
        Interpreting plasma estrogen levels in breast cancer: caution needed.
        J Clin Oncol. 2014; 32: 1396-1400
        • Qureshi R
        • Picon-Ruiz M
        • Aurrekoetxea-Rodriguez I
        • et al.
        The major pre- and postmenopausal estrogens play opposing roles in obesity-driven mammary inflammation and breast cancer development.
        Cell Metab. 2020; 31 (e9): 1154-1172
        • Sestak I
        • Distler W
        • Forbes JF
        • Dowsett M
        • Howell A
        • Cuzick J.
        Effect of body mass index on recurrences in tamoxifen and anastrozole treated women: an exploratory analysis from the ATAC trial.
        J Clin Oncol. 2010; 28: 3411-3415
        • Gnant M
        • Pfeiler G
        • Stoger H
        • et al.
        The predictive impact of body mass index on the efficacy of extended adjuvant endocrine treatment with anastrozole in postmenopausal patients with breast cancer: an analysis of the randomised ABCSG-6a trial.
        Br J Cancer. 2013; 109: 589-596
        • Pfeiler G
        • Konigsberg R
        • Hadji P
        • et al.
        Impact of body mass index on estradiol depletion by aromatase inhibitors in postmenopausal women with early breast cancer.
        Br J Cancer. 2013; 109: 1522-1527
        • Lintermans A
        • Vanderschueren D
        • Verhaeghe J
        • et al.
        Arthralgia induced by endocrine treatment for breast cancer: a prospective study of serum levels of insulin like growth factor-I, its binding protein and oestrogens.
        Eur J Cancer. 2014; 50: 2925-2931
        • Lonning PE
        • Haynes BP
        • Dowsett M.
        Relationship of body mass index with aromatisation and plasma and tissue oestrogen levels in postmenopausal breast cancer patients treated with aromatase inhibitors.
        Eur J Cancer. 2014; 50: 1055-1064