Safety of 5α-reductase inhibitors and spironolactone in breast cancer patients receiving endocrine therapies
To provide dermatologists and oncologists with a foundation for practical understanding and uses of 5α-reductase inhibitors and spironolactone for breast cancer patients and survivors receiving endocrine therapies (ETs), including the effect of these treatments on sex hormone levels, any reported drug interactions, and any risk of malignancy.
All published studies from January 1978 through April 2018 were considered, using databases such as PubMed, Google Scholar, and Science Direct. Forty-seven studies were included in this review.
There is no evidence of interactions between 5α-reductase inhibitors and spironolactone with ETs used in breast cancer. Sex hormone alteration with 5α-reductase inhibitor or spironolactone use is variable. Three randomized controlled trials, 1 case–control study, and 6 retrospective cohort studies, including 284 female patients, studied the effects of 5α-reductase inhibitors on serum estrogen levels. Levels were increased in 97 of 284 (34%) patients, decreased in 15 of 284 (5.3%) patients, and unchanged in 162 of 284 (57%) patients. Four retrospective cohort studies, 1 case study, and 1 double-blinded crossover study, including 95 female patients, assessed the effect of spironolactone on estrogen levels. Levels were increased in 25 of 95 (26%) patients, decreased in 6 of 95 (6.3%) patients, and unchanged in 64 of 95 (67%) patients. Ultimately, most patients did not have a significant alteration in the level of estrogen when using 5α-reductase inhibitors or spironolactone. No consistent evidence of increased risk of female breast cancer while on spironolactone was reported in 3 studies including 49,298 patients; the risk of breast cancer with the use of 5α-reductase inhibitors has not been studied.
Most patients did not show increased estrogen levels with spironolactone and there were no data suggesting increased risk of breast cancer. Based on hormonal and pharmacological activity, spironolactone may be considered for further research on alopecia and hirsutism in breast cancer patients.
Keywords5α-Reductase inhibitors Spironolactone Female pattern hair loss Female breast cancer Endocrine therapy
This study was supported in part by the NIH/NCI Cancer Center Support Grant P30 CA008748. This research was additionally funded in part by Beca Excelencia Fundación Piel Sana (Dr. Freites-Martinez) and the RJR Grant. The sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of data; in the preparation, review, or approval of the manuscript; or in the decision to submit the manuscript for publication.
Compliance with ethical standards
Conflict of interest
The authors declare no conflicts of interest with regard to the preparation of this manuscript.
Mario E. Lacouture has no relevant conflicts of interest with regard to preparation of this manuscript. He has served as consultant for Legacy, Adgero, Debiopharm,Galderma, Johnson and Johnson, Novocure Inc., Merck, Helsinn, Janssen, Menlo Ther, Novartis, Roche, Abbvie, Boehringer Ingelheim, Amgen, E.R. Squibb & Sons, EMD Serono, Genentech, Seattle Genetics, Bayer, Manner SAS, Lutris, Paxman Coolers, Pfizer, Bristol-Myers Squibb, Silk Therapeutics, Foamix, and Medische Voet. He has received research funding from GSK, Novartis, Veloce, US Biotest, Berg, Bristol-Myers Squibb. Eliza B. Geer has no relevant conflicts of interest with regard to preparation of this manuscript. She has served as the principal investigator of research grants to MSKCC from Novartis, Strongbridge, Chiasma, and IONIS and has received occasional consulting honoraria from Novartis, Strongbridge, Corcept, and Pfizer. Jerry Shapiro has no relevant conflicts of interest with regard to preparation of this manuscript. He has served as a consultant for Aclaris, Samumed, Incyte, Replicel Life Sciences, and Shook, Hardy, Bacon LLP who represent Sanofi Aventis US LLC.
This article does not contain any studies with human participants performed by any of the authors.
- 1.World Health Organization. WHO | breast cancer: prevention and control. http://www.who.int/cancer/detection/breastcancer/en/. Accessed 26 Nov 2017
- 6.Freites-Martinez A, Shapiro J, van den Hurk C, et al (2018) CME part 2: hair disorders in cancer survivors persistent chemotherapy-induced alopecia, persistent radiotherapy-induced alopecia, and hair growth disorders related to endocrine therapy or cancer surgery. J Am Acad Dermatol. https://doi.org/10.1016/j.jaad.2018.03.056 PubMedGoogle Scholar
- 8.Bourgeois H, Kerbrat P, Combe M et al (2010) Long term persistent alopecia and suboptimal hair regrowth after adjuvant chemotherapy for breast cancer: alert for an emerging side effect: French ALOPERS Observatory. Ann Oncol 21:83–84Google Scholar
- 9.Kang D, Kim IR, Lee D et al (2017) Incidence of permanent chemotherapy-induced alopecia among breast cancer patients: a five-year prospective cohort study. Ann Oncol 28:22Google Scholar
- 10.Kim S, Park H, Kim J et al (2016) Irreversible chemotherapy-induced alopecia in breast cancer patient. Cancer Res. https://doi.org/10.1158/1538-7445.SABCS15-P1-15-04 Google Scholar
- 12.Bertrand M, Mailliez A, Vercambre S, Kotecki N, Mortier L, Bonneterre J(2013) Permanent chemotherapy induced alopecia in early breast cancer patients after (neo)adjuvant chemotherapy: long term follow up. Cancer Res. https://doi.org/10.1158/0008-5472.SABCS13-P3-09-15 Google Scholar
- 13.Fonia A, Cota C, Setterfield JF, Goldberg LJ, Fenton DA, Stefanato CM (2017) Permanent alopecia in patients with breast cancer after taxane chemotherapy and adjuvant hormonal therapy: clinicopathologic findings in a cohort of 10 patients. J Am Acad Dermatol 76(5):948–957. https://doi.org/10.1016/j.jaad.2016.12.027 PubMedGoogle Scholar
- 14.Kluger N, Jacot W, Frouin E et al (2012) Permanent scalp alopecia related to breast cancer chemotherapy by sequential fluorouracil/epirubicin/cyclophosphamide (FEC) and docetaxel: a prospective study of 20 patients. Ann Oncol 23(11):2879–2884. https://doi.org/10.1093/annonc/mds095. Epub 9 May 2012PubMedGoogle Scholar
- 15.Thorp N, Swift F, Arundell D, Wong H (2015) Long term hair loss in patients with early breast cancer receiving docetaxel chemotherapy. Cancer Res. https://doi.org/10.1158/1538-7445.SABCS14-P5-17-04 Google Scholar
- 16.Otberg N, Shapiro J (2012) Chapter 88. Hair growth disorders. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K (eds) Fitzpatrick’s dermatology in general medicine, 8th edn. The McGraw-Hill Companies, New York. http://accessmedicine.mhmedical.com/content.aspx?aid=56049509. Accessed 25 March 2018
- 23.Gupta AK, Charrette A (2014) The efficacy and safety of 5α-reductase inhibitors in androgenetic alopecia: a network meta-analysis and benefit-risk assessment of finasteride and dutasteride. J Dermatol Treat 25(2):156–161. https://doi.org/10.3109/09546634.2013.813011. Accessed 26 March 2018PubMedGoogle Scholar
- 26.Mella JM, Perret MC, Manzotti M, Catalano HN, Guyatt G (2010) Efficacy and safety of finasteride therapy for androgenetic alopecia: a systematic review. Arch Dermatol 146(10):1141–1150. https://doi.org/10.1001/archdermatol.2010.256. Accessed 26 March 2018
- 27.Iorizzo M, Vincenzi C, Voudouris S, Piraccini BM, Tosti A (2006) Finasteride treatment of female pattern hair loss. Arch Dermatol 142(3):298–302. https://doi.org/10.1001/archderm.142.3.298. Accessed 26 March 2018
- 31.Castello R, Tosi F, Perrone F, Negri C, Muggeo M, Moghetti P (1996) Outcome of long-term treatment with the 5 alpha-reductase inhibitor finasteride in idiopathic hirsutism: clinical and hormonal effects during a 1-year course of therapy and 1-year follow-up. Fertil Steril 66(5):734–740. http://www.ncbi.nlm.nih.gov/pubmed/8893676
- 32.Venturoli S, Marescalchi O, Colombo FM et al (1999) A prospective randomized trial comparing low dose flutamide, finasteride, ketoconazole, and cyproterone acetate-estrogen regimens in the treatment of hirsutism. J Clin Endocrinol Metab 84(4):1304–1310. https://doi.org/10.1210/jcem.84.4.5591 PubMedGoogle Scholar
- 41.Conrad F, Ohnemus U, Bodo E et al (2005) Substantial sex-dependent differences in the response of human scalp hair follicles to estrogen stimulation in vitro advocate gender-tailored management of female versus male pattern balding. J Investig Dermatol Symp Proc 10(3):243–246. https://doi.org/10.1111/j.1087-0024.2005.10115.x.Accessed 31 May 2018
- 56.Ciotta L, Cianci A, Calogero AE et al (1995) Clinical and endocrine effects of finasteride, a 5 alpha-reductase inhibitor, in women with idiopathic hirsutism. Fertil Steril 64(2):299–306. http://www.ncbi.nlm.nih.gov/pubmed/7615107
- 57.Bayhan G, Bahceci M, Demirkol T, Ertem M, Yalinkaya A, Erden AC (2000) A comparative study of a gonadotropin-releasing hormone agonist and finasteride on idiopathic hirsutism. Clin Exp Obstet Gynecol 27(3–4):203–206. http://www.ncbi.nlm.nih.gov/pubmed/11214952
- 70.Olsen EA, Hordinsky M, Whiting D et al (2006) The importance of dual 5alpha-reductase inhibition in the treatment of male pattern hair loss: results of a randomized placebo-controlled study of dutasteride versus finasteride. J Am Acad Dermatol 55(6):1014–1023. https://doi.org/10.1016/j.jaad.2006.05.007 PubMedGoogle Scholar
- 84.Ganie MA, Khurana ML, Nisar S et al (2013) Improved efficacy of low-dose spironolactone and metformin combination than either drug alone in the management of women with polycystic ovary syndrome (PCOS): a six-month, open-label randomized study. J Clin Endocrinol Metab 98(9):3599–3607. https://doi.org/10.1210/jc.2013-1040. Epub 11 July 2013PubMedGoogle Scholar
- 87.Milewicz A, Silber D, Kirschner MA (1983) Therapeutic effects of spironolactone in polycystic ovary syndrome. Obstet Gynecol 61(4):429–432. http://www.ncbi.nlm.nih.gov/pubmed/6828272
- 88.Lobo RA, Shoupe D, Serafini P, Brinton D, Horton R (1985) The effects of two doses of spironolactone on serum androgens and anagen hair in hirsute women. Fertil Steril 43(2):200–205. http://www.ncbi.nlm.nih.gov/pubmed/3967781
- 95.Sert M, Tetiker T, Kirim S (2003) Comparison of the efficiency of anti-androgenic regimens consisting of spironolactone, Diane 35, and cyproterone acetate in hirsutism. Acta Med Okayama 57(2):73–76. http://www.ncbi.nlm.nih.gov/pubmed/12866746
- 99.Some thyrotropic agents (2001) IARC monographs on the evaluation of carcinogenic risks to humans, No. 79, p 725Google Scholar
- 103.Hsu C, Liu J, Lin A, Yang C, Chung W, Wu W (2014) Minoxidil may suppress androgen receptor-related functions. OncoTarget 5(8):2187–2197. https://doi.org/10.18632/oncotarget.1886. Accessed 7 April 2018
- 105.Buhl AE (1991) Minoxidil’s action in hair follicles. J Investig Dermatol 96(5):74SGoogle Scholar
- 109.Tolino A, Petrone A, Sarnacchiaro F et al (1996) Finasteride in the treatment of hirsutism: new therapeutic perspectives. Fertil Steril 66(1):61–65. http://www.ncbi.nlm.nih.gov/pubmed/8752612