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A randomized, double-blind, placebo-controlled trial of testosterone for treatment of postmenopausal women with aromatase inhibitor-induced arthralgias: Alliance study A221102

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Abstract

Purpose

To evaluate the efficacy of testosterone supplementation for improving aromatase inhibitor musculoskeletal symptoms (AIMSS).

Methods

Postmenopausal women experiencing moderate-to-severe arthralgias while taking adjuvant aromatase inhibitors for breast cancer were enrolled in this trial. Initially, patients were randomly allocated to receive either a subcutaneous testosterone pellet versus a placebo pellet. Due to slow accrual, the protocol was modified such that additional participants were randomized to receive either a topical testosterone gel or a placebo gel. Changes in patient-reported joint pain were compared between patients receiving testosterone and those receiving placebo using a two-sample t test. Changes in hot flashes and other vasomotor symptoms were also analyzed. Further analyses were conducted to evaluate whether 27 single nucleotide polymorphisms (SNPs) in 14 genes previously associated with AIMSS were associated with testosterone supplementation benefit.

Results

While 64% of patients reported an improvement in joint pain at 3 months, there were no significant differences in average pain or joint stiffness at 3 or 6 months between testosterone and placebo arms. Patients receiving testosterone did report improvements in strength, lack of energy, urinary frequency, and stress incontinence (p < 0.05). The subset of patients receiving subcutaneous testosterone also experienced improvements in hot flashes and mood swings. An inherited variant (rs7984870 CC genotype) in TNFSF11 was more likely to be associated with improvements in hot flashes in patients receiving testosterone.

Conclusion

The doses of testosterone supplementation used in this study did not significantly improve AIMSS.

Trial registration

ClinicalTrials.gov Identifier: NCT01573442

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Funding

The research reported in this publication was financially supported by the National Cancer Institute of the National Institutes of Health under the Award Number UG1CA189823 (Alliance for Clinical Trials in Oncology NCORP Grant), UG1CA232760, U24CA196171, UG1CA189858, UG1CA189997, U10CA180820, and UG1CA189861 (ECOG-ACRIN), U10CA180868 (NRG), and U24CA196171, as well as the Alliance biorepository resource.

Author information

Authors and Affiliations

  1. Mayo Clinic, Rochester, MN, USA

    Elizabeth Cathcart-Rake, Roberto Leon-Ferre, Araba A. Adjei, Jacqueline M. Lafky & Charles L. Loprinzi

  2. Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA

    Paul Novotny, Jennifer Le-Rademacher & Elizabeth M. Storrick

  3. Sanford NCORP of the North Central Plains, Sioux Falls, SD, USA

    Shelby Terstriep

  4. Wright State University Boonshoft School of Medicine, Dayton, OH, USA

    Rebecca Glaser

  5. Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Armando Giuliano

  6. Southeast Clinical Oncology Research Consortium NCORP, Winston-Salem, NC, USA

    William R. Mitchell

  7. Wichita NCI Community Oncology Research Program, Wichita, KS, USA

    Seth Page

  8. Northside Hospital, Atlanta, GA, USA

    Colleen Austin & Margaret A. Ferreira

  9. Mercy Medical Center, Des Moines, IA, USA

    Richard L. Deming

  10. The Breast and Endocrine Centre, Toorak Gardens, South Australia, Australia

    Stephen N. Birrell

  11. Department of Medical Oncology, Mayo Clinic, 200 First St SW, Rochester, MN, USA

    Charles L. Loprinzi

Authors
  1. Elizabeth Cathcart-Rake
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  2. Paul Novotny
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  3. Roberto Leon-Ferre
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  4. Jennifer Le-Rademacher
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  10. William R. Mitchell
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  11. Seth Page
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  12. Colleen Austin
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  15. Jacqueline M. Lafky
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  16. Stephen N. Birrell
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  17. Charles L. Loprinzi
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Corresponding author

Correspondence to Charles L. Loprinzi.

Ethics declarations

Conflict of interest

The US NCI provided funding for this trial.

The authors have no financial relationship with any private company regarding this research with the exception that Dr. Birrell reports personal fees from Havah Therapeutics, that is developing androgen-based therapies for women, and has a patent AU2005905768A0; additionally, Dr. Glaser has a patent (US 10,071,104 B2) related to this topic.

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Clinical relevance

This study evaluates whether testosterone therapy improves the widespread clinical problem of aromatase inhibitor musculoskeletal symptoms.

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Cathcart-Rake, E., Novotny, P., Leon-Ferre, R. et al. A randomized, double-blind, placebo-controlled trial of testosterone for treatment of postmenopausal women with aromatase inhibitor-induced arthralgias: Alliance study A221102. Support Care Cancer 29, 387–396 (2021). https://doi.org/10.1007/s00520-020-05473-2

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