Debunking Myths and Examining Evidence
Breast cancer survivors often face a myriad of challenges, including managing symptoms related to breast cancer treatment. One controversial topic is the use of testosterone in this population. Let’s explore the evidence and shed light on whether testosterone is safe for breast cancer survivors.
1. New Onset Breast Cancer with Testosterone Treatment
A groundbreaking 10-year cohort study investigated the incidence of invasive breast cancer (IBC) in women treated with subcutaneous testosterone implants or testosterone implants combined with anastrozole (an aromatase inhibitor). The study found that long-term therapy with subcutaneous testosterone did not increase the risk of IBC. In fact, the incidence rate of IBC was significantly lower in the testosterone-treated group compared to age-matched expected rates. This suggests that testosterone therapy may actually have a protective effect on breast tissue (1).
Another study, published in April 2024, analyzed claims data of over 16,000 females on testosterone versus matched controls from 2009 to 2022. Those on testosterone had significantly lower risk of major cardiac events, blood clots, and breast cancer than the controls. The lower risk of breast cancer was especially pronounced in participants over age 55 (2).
Another prospective trial of 1268 pre- and postmenopausal women treated with testosterone therapy with or without anastrozole (a breast cancer treatment). The study found that both testosterone alone and testosterone with anastrozole decreased the risk of developing breast cancer. Participants who reported more regular use of testosterone therapy were found to have especially low rates of breast cancer - only 73 cases per 100,000 women per year, as apposed to 300 cases per 100,000 women per year for controls. Interestingly, of the 5 cases of cancer in the testosterone therapy group with available labs, the testosterone levels were all below average (3).
Yet another study, going back to 2004, looked at the incidence of breast cancer in women treated with testosterone in addition to usual menopausal hormone therapy, for an average of 5.8 years. Breast cancer incidence was lower in the group taking testosterone plus hormone therapy than in similar populations taking usual hormone therapy (estrogen plus progestin), and was similar to populations who had never used hormone therapy (4).
2. Vaginal Testosterone Cream vs. Estradiol Vaginal Ring
One randomized clinical trial explored the use of vaginal testosterone cream versus an estradiol vaginal ring in women receiving aromatase inhibitors for early-stage breast cancer. The goal was to address vaginal dryness and decreased libido. Both the vaginal ring and intra-vaginal testosterone (IVT) met the primary safety end point with 12% estradiol elevations with IVT compared with none with the vaginal ring (5).
Supplement use or aromatase inhibitor compliance may have contributed to estradiol variations, but this data was not formally collected. Both the vaginal ring and IVT improved vaginal atrophy, sexual interest, and desire.
3. Investigating Testosterone for Side Effects From Breast Cancer Treatment
The Alliance study A221102 was a randomized, double-blind, placebo-controlled trial that evaluated the efficacy of testosterone supplementation in improving aromatase inhibitor musculoskeletal symptoms (AIMSS) in postmenopausal women. These symptoms, including joint pain and stiffness, often occur as side effects of aromatase inhibitors (such as anastrozole or letrozole) used in breast cancer treatment (6).
Study Design and Participants
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 or a placebo pellet.
Due to slow accrual, the protocol was modified, and additional participants were randomized to receive either a topical testosterone gel or a placebo gel.
Key Findings
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 the 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.
Although the doses of testosterone supplementation used in this study did not significantly improve AIMSS, there were several other benefits demonstrated in postmenopausal women.
5. Can Testosterone Safely Be Used During Breast Cancer Treatment?
A September 2024 pilot study of 29 women undergoing ovarian suppression for breast cancer examined the safety of a topical testosterone. Testosterone gel at 3 mg per day was applied, along with aromatase inhibitors to block the conversion of testosterone to estrogen. Not only was the safety endpoint met, with no increase in estrogen levels detected, but also sexual function significantly improved over the course of the three month study (6). There were improvements in desire, arousal, lubrication, orgasm, and satisfaction, but the maximum effect wasn't reached until the 3rd month of treatment (7).
A 2021 review article found the treatment with testosterone can improve all 11 symptoms on the Menopause Rating Scale in patients with breast cancer (8).
5. Has Testosterone Been Used as a Treatment for Breast Cancer?
Indeed, it has. A 2014 case report looked at treatment with pellets containing both testosterone and anastrozole (a breast cancer treatment) inserted directly into the breast tissue around a tumor. This 90-year-old patient had previously failed treatment with tamoxifen. She underwent serial imaging of her breast after testosterone + anastrozole pellet injections. 46 days later her cancer was markedly reduced in size, from 5.12 cm3 to 0.74 cm3. She received another treatment at that time. On week 13, the tumor volume had reduced to 0.42 cm3. The patient reported that she felt better than she had in years, stopped using her walker, and began driving her car again (9)!
Glaser and Dimitrakakis (2021) reported another case of breast cancer remission in a 58 year old woman who chose to forego conventional breast cancer therapy. She was treated with testosterone and letrozole pellets alone. She also made dietary changes. There was a complete clinical response by 14 weeks, and she remained disease-free after two years of continued treatment (8).
Conclusion: Reconsidering Testosterone
While caution is essential, emerging evidence suggests that testosterone can be safely used in breast cancer survivors. Collaborative studies and individualized approaches are crucial. As we continue to explore the interplay between hormones and cancer, testosterone should be further investigated for hormone therapy and breast cancer prevention.
Remember to consult your healthcare provider before making any decisions regarding testosterone therapy. Each survivor’s situation is unique, and personalized care is essential.
References:
Glaser, R., York, A. E., & Dimitrakakis, C. (2019). Incidence of invasive breast cancer in women treated with testosterone implants: a prospective 10-year cohort study. BMC Cancer, 19, 1271. Read the full study.
Agrawal P, Singh SM, Hsueh J, Grutman A, An C, Able C, Choi U, Kohn J, Clifton M, Kohn TP. Testosterone therapy in females is not associated with increased cardiovascular or breast cancer risk: a claims database analysis. J Sex Med. 2024 Apr 30;21(5):414-419. doi: 10.1093/jsxmed/qdae032. PMID: 38459625.
Glaser RL, Dimitrakakis C. Reduced breast cancer incidence in women treated with subcutaneous testosterone, or testosterone with anastrozole: a prospective, observational study. Maturitas. 2013 Dec;76(4):342-9. doi: 10.1016/j.maturitas.2013.08.002. Epub 2013 Sep 10. PMID: 24028858.
Dimitrakakis C, Jones RA, Liu A, Bondy CA. Breast cancer incidence in postmenopausal women using testosterone in addition to usual hormone therapy. Menopause. 2004 Sep-Oct;11(5):531-5. doi: 10.1097/01.gme.0000119983.48235.d3. PMID: 15356405.
Melisko ME, Goldman ME, Hwang J, De Luca A, Fang S, Esserman LJ, Chien AJ, Park JW, Rugo HS. Vaginal Testosterone Cream vs Estradiol Vaginal Ring for Vaginal Dryness or Decreased Libido in Women Receiving Aromatase Inhibitors for Early-Stage Breast Cancer: A Randomized Clinical Trial. JAMA Oncol. 2017 Mar 1;3(3):313-319. doi: 10.1001/jamaoncol.2016.3904. Erratum in: JAMA Oncol. 2020 Sep 1;6(9):1473. Read the full study.
Cathcart-Rake, E., Novotny, P., Leon-Ferre, R., Le-Rademacher, J., Storrick, E. M., Adjei, A. A., … & Loprinzi, C. L. (2021). A randomized, double-blind, placebo-controlled trial of testosterone for treatment of postmenopausal women with aromatase inhibitor-induced arthralgias: Alliance study A221102. Supportive Care in Cancer, 29(1), 387-396. Read the full study.
Taranto P, de Brito Sales D, Maluf FC, Guendelmann RAK, de Melo Pompei L, Leal A, Buzaid AC, Schvartsman G. Safety and efficacy of topical testosterone in breast cancer patients receiving ovarian suppression and aromatase inhibitor therapy. Breast Cancer Res. 2024 Sep 16;26(1):133. doi: 10.1186/s13058-024-01886-7. PMID: 39285489; PMCID: PMC11403844.
Glaser, R., & Dimitrakakis, C. (2021). Testosterone implant therapy in women with and without breast cancer: Rationale, experience, evidence. Androgens: Clinical Research and Therapeutics, 2(1), 94-110. https://doi.org/10.1089/andro.2021.0003
Glaser RL, Dimitrakakis C. Rapid response of breast cancer to neoadjuvant intramammary testosterone-anastrozole therapy: neoadjuvant hormone therapy in breast cancer. Menopause. 2014 Jun;21(6):673-8. doi: 10.1097/GME.0000000000000096. PMID: 24149917; PMCID: PMC4033664.
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