Supportive Care in Cancer

, Volume 26, Issue 8, pp 2561–2569 | Cite as

L-Thyroxine intake as a potential risk factor for the development of fatigue in breast cancer patients undergoing chemotherapy

  • Martina E. SchmidtEmail author
  • Joachim Wiskemann
  • Theron Johnson
  • Nina Habermann
  • Andreas Schneeweiss
  • Karen Steindorf
Original Article



L-Thyroxine is one of the most commonly prescribed drugs and accordingly used by many breast cancer patients with thyroid disorders. Hence, potential interactions of chemotherapy with L-thyroxine, possibly contributing to fatigue, would be of high clinical relevance. Therefore, we investigated fatigue and underlying pathways in L-thyroxine-using breast cancer patients during chemotherapy.


Thyroid-stimulating hormone (TSH), L-triiodothyronine (T3), and diurnal salivary cortisol patterns were analyzed in breast cancer patients in the beginning and at the end of adjuvant chemotherapy within the control group (n = 41) of a randomized exercise intervention trial. Additionally, relationships in the exercising group (n = 45) as well as in healthy women (n = 25) were explored. Regression and mediation analyses were performed.


L-Thyroxine use was significantly associated with lower TSH (median = 0.33 mU/l, interquartile range = (0.15–0.48)), whereas patients not using L-thyroxine had TSH comparable to healthy women (0.51 mU/l (0.37–0.74)). T3 significantly declined during chemotherapy in L-thyroxine users but not in non-users. However, the group difference failed statistical significance. L-Thyroxine treatment was significantly associated with increased physical fatigue during chemotherapy (p = 0.004) in the non-exercising group. This association appeared to be partly mediated by TSH. Further, TSH appeared to affect fatigue partly via increased cortisol levels. In the exercise group, there was no significant association between L-thyroxine and fatigue.


L-Thyroxine treatment during chemotherapy might result in hormonal dysregulations that can contribute to increased physical fatigue. Therefore, breast cancer patients on L-thyroxine treatment may need special monitoring of their thyroid levels and of fatigue during chemotherapy and should be encouraged to exercise.

Trial registration: NCT01106820.


Fatigue Levothyroxine Chemotherapy Thyroid function Cortisol Breast cancer 



We thank Petra Armbrust for study assistance, Christine Niesik, Lin Zielske, Marita Wenzel, and Anett Brendel for technical support in the lab and Dr. Dr. Philipp Zimmer for valuable comments to the manuscript. The foundation “Stiftung Leben mit Krebs” partially supported the intervention programs.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The BEATE and INVEST studies were approved by the Ethics Committee of the University of Heidelberg. All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional and/or National Research Committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Schmidt ME, Chang-Claude J, Seibold P, Vrieling A, Heinz J, Flesch-Janys D, Steindorf K (2015) Determinants of long-term fatigue in breast cancer survivors: results of a prospective patient cohort study. Psycho-Oncology 24:40–46. CrossRefPubMedGoogle Scholar
  2. 2.
    Bower JE (2014) Cancer-related fatigue—mechanisms, risk factors, and treatments. Nat Rev Clin Oncol 11(10):597–609. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Schmidt ME, Wiskemann J, Armbrust P, Schneeweiss A, Ulrich CM, Steindorf K (2015) Effects of resistance exercise on fatigue and quality of life in breast cancer patients undergoing adjuvant chemotherapy: a randomized controlled trial. Int J Cancer 137(2):471–480. CrossRefPubMedGoogle Scholar
  4. 4.
    Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, Cooper DS, Kim BW, Peeters RP, Rosenthal MS, Sawka AM, American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid 24(12):1670–1751. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Taylor PN, Iqbal A, Minassian C, Sayers A, Draman MS, Greenwood R, Hamilton W, Okosieme O, Panicker V, Thomas SL, Dayan C (2014) Falling threshold for treatment of borderline elevated thyrotropin levels-balancing benefits and risks: evidence from a large community-based study. JAMA Intern Med 174(1):32–39. CrossRefPubMedGoogle Scholar
  6. 6.
    Schmidt ME, Semik J, Habermann N, Wiskemann J, Ulrich CM, Steindorf K (2016) Cancer-related fatigue shows a stable association with diurnal cortisol dysregulation in breast cancer patients. Brain Behav Immun 52:98–105. CrossRefPubMedGoogle Scholar
  7. 7.
    Furmaniak AC, Menig M, Markes MH (2016) Exercise for women receiving adjuvant therapy for breast cancer. Cochrane Database of Syst Rev 9:CD005001. CrossRefGoogle Scholar
  8. 8.
    Schmidt ME, Wiskemann J, Armbrust P, Schneeweiss A, Ulrich CM, Steindorf K (2014) Effects of resistance exercise on fatigue and quality of life in breast cancer patients undergoing adjuvant chemotherapy: a randomized controlled trial. Int J CancerGoogle Scholar
  9. 9.
    Schmidt ME, Wiskemann J, Krakowski-Roosen H, Knicker AJ, Habermann N, Schneeweiss A, Ulrich CM, Steindorf K (2013) Progressive resistance versus relaxation training for breast cancer patients during adjuvant chemotherapy: design and rationale of a randomized controlled trial (BEATE study). Contemp Clin Trials 34(1):117–125. CrossRefPubMedGoogle Scholar
  10. 10.
    Beutel ME, Hinz A, Albani C, Brahler E (2006) Fatigue assessment questionnaire: standardization of a cancer-specific instrument based on the general population. Oncology 70(5):351–357CrossRefPubMedGoogle Scholar
  11. 11.
    MacKinnon DP, Luecken LJ (2011) Statistical analysis for identifying mediating variables in public health dentistry interventions. J Public Health Dent 71(Suppl 1):S37–S46CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Baron RM, Kenny DA (1986) The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol 51(6):1173–1182CrossRefPubMedGoogle Scholar
  13. 13.
    Huang JB, Jin LB, Ji GG, Xing L, Xu CB, Xiong X et al (2013) Implication from thyroid function decreasing during chemotherapy in breast cancer patients: chemosensitization role of triiodothyronine. BMC Cancer 13:334. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Kumar N, Allen KA, Riccardi D, Bercu BB, Cantor A, Minton S, Balducci L, Jacobsen PB (2004) Fatigue, weight gain, lethargy and amenorrhea in breast cancer patients on chemotherapy: is subclinical hypothyroidism the culprit? Breast Cancer Res Treat 83(2):149–159. CrossRefPubMedGoogle Scholar
  15. 15.
    de Groot S, Janssen LGM, Charehbili A, Dijkgraaf EM, Smit VTHBM, Kessels LW, van Bochove A, van Laarhoven HWM, Meershoek-Klein Kranenbarg E, van Leeuwen-Stok AE, van de Velde CJH, Putter H, Nortier JWR, van der Hoeven JJM, Pijl H, Kroep JR (2015) Thyroid function alters during neoadjuvant chemotherapy in breast cancer patients: results from the NEOZOTAC trial (BOOG 2010-01). Breast Cancer Res Treat 149(2):461–466. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    van de Ven AC, Netea-Maier RT, de Vegt F, Ross HA, Sweep FC, Kiemeney LA et al (2012) Is there a relationship between fatigue perception and the serum levels of thyrotropin and free thyroxine in euthyroid subjects? Thyroid: Off J Am Thyroid Assoc 22(12):1236–1243. CrossRefGoogle Scholar
  17. 17.
    McAninch EA, Bianco AC (2014) Thyroid hormone signaling in energy homeostasis and energy metabolism. Ann N Y Acad Sci 1311:77–87. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Salvatore D, Simonides WS, Dentice M, Zavacki AM, Larsen PR (2014) Thyroid hormones and skeletal muscle—new insights and potential implications. Nat Rev Endocrinol 10(4):206–214. CrossRefPubMedGoogle Scholar
  19. 19.
    Lombardi A, Moreno M, de Lange P, Iossa S, Busiello RA, Goglia F (2015) Regulation of skeletal muscle mitochondrial activity by thyroid hormones: focus on the “old” triiodothyronine and the “emerging” 3,5-diiodothyronine. Front Physiol 6:237. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Berger AM, Mooney K, Alvarez-Perez A, Breitbart WS, Carpenter KM, Cella D, Cleeland C, Dotan E, Eisenberger MA, Escalante CP, Jacobsen PB, Jankowski C, LeBlanc T, Ligibel JA, Loggers ET, Mandrell B, Murphy BA, Palesh O, Pirl WF, Plaxe SC, Riba MB, Rugo HS, Salvador C, Wagner LI, Wagner-Johnston ND, Zachariah FJ, Bergman MA, Smith C, National comprehensive cancer network (2015) Cancer-related fatigue, version 2.2015. J Natl Compr Canc Netw: JNCCN 13(8):1012–1039CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Schmidt ME, Wiskemann J, Schneeweiss A, Potthoff K, Ulrich CM, Steindorf K (2017) Determinants of physical, affective, and cognitive fatigue during breast cancer therapy and 12 months follow-up. Int J Cancer 142:1148–1157. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Martina E. Schmidt
    • 1
    Email author
  • Joachim Wiskemann
    • 2
  • Theron Johnson
    • 3
  • Nina Habermann
    • 4
  • Andreas Schneeweiss
    • 2
  • Karen Steindorf
    • 1
  1. 1.Division of Physical Activity, Prevention and CancerGerman Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT)HeidelbergGermany
  2. 2.Division of Medical OncologyUniversity Clinic Heidelberg and National Center for Tumor Diseases (NCT)HeidelbergGermany
  3. 3.Division of Cancer EpidemiologyGerman Cancer Research Center (DKFZ)HeidelbergGermany
  4. 4.Genome BiologyEuropean Molecular Biology Laboratory (EMBL)HeidelbergGermany

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