Testosterone replacement in young male cancer survivors: A 6-month double-blind randomised placebo-controlled trial

English version

Autoři: Jennifer S. Walsh ^aff001; Helen Marshall ^aff002; Isabelle L. Smith ^aff002; Diana M. Greenfield ^aff003; Jayne Swain ^aff002; Emma Best ^aff002; James Ashton ^aff004; Julia M. Brown ^aff002; Robert Huddart ^aff005; Robert E. Coleman ^aff001; John A. Snowden ^aff006; Richard J. Ross ^aff001
Působiště autorů: Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom ^aff001; Clinical Trials Research Unit, University of Leeds, Leeds, United Kingdom ^aff002; Specialised Cancer Services, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom ^aff003; TRYMS Trial Management Group, Sheffield, United Kingdom ^aff004; Institute for Cancer Research, London, United Kingdom ^aff005; Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom ^aff006
Vyšlo v časopise: Testosterone replacement in young male cancer survivors: A 6-month double-blind randomised placebo-controlled trial. PLoS Med 16(11): e1002960. doi:10.1371/journal.pmed.1002960
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pmed.1002960

Souhrn

Background

Young male cancer survivors have lower testosterone levels, higher fat mass, and worse quality of life (QoL) than age-matched healthy controls. Low testosterone in cancer survivors can be due to orchidectomy or effects of chemotherapy and radiotherapy. We have undertaken a double-blind, placebo-controlled, 6-month trial of testosterone replacement in young male cancer survivors with borderline low testosterone (7–12 nmol/l).

Methods and findings

This was a multicentre United Kingdom study conducted in secondary care hospital outpatients. Male survivors of testicular cancer, lymphoma, and leukaemia aged 25–50 years with morning total serum testosterone 7–12 nmol/l were recruited. A total of 136 men were randomised between July 2012 and February 2015 (42.6% aged 25–37 years, 57.4% 38–50 years, 88% testicular cancer, 10% lymphoma, matched for body mass index [BMI]). Participants were randomised 1:1 to receive testosterone (Tostran 2% gel) or placebo for 26 weeks. A dose titration was performed after 2 weeks. The coprimary end points were trunk fat mass and SF36 Physical Functioning score (SF36-PF) at 26 weeks by intention to treat. At 26 weeks, testosterone treatment compared with placebo was associated with decreased trunk fat mass (−0.9 kg, 95% CI −1.6 to −0.3, p = 0.0073), decreased whole-body fat mass (−1.8 kg, 95% CI −2.9 to −0.7, p = 0.0016), and increased lean body mass (1.5 kg, 95% CI 0.9–2.1, p < 0.001). Decrease in fat mass was greatest in those with a high truncal fat mass at baseline. There was no treatment effect on SF36-PF or any other QoL scores. Testosterone treatment was well tolerated. The limitations of our study were as follows: a relatively short duration of treatment, only three cancer groups included, and no hard end point data such as cardiovascular events.

Conclusions

In young male cancer survivors with low-normal morning total serum testosterone, replacement with testosterone is associated with an improvement in body composition.

Trial registration

ISRCTN: 70274195, EudraCT: 2011-000677-31.

Klíčová slova:

Cancer treatment – Fats – Adverse events – Testosterone – Lymphomas – Fatigue – Testicular cancer

Zdroje

1. Sklar CA, Antal Z, Chemaitilly W, Cohen LE, Follin C, Meacham LR, et al. Hypothalamic-Pituitary and Growth Disorders in Survivors of Childhood Cancer: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(8):2761–84. Epub 2018/07/10. doi: 10.1210/jc.2018-01175 29982476. 29982476

2. Oeffinger KC, Mertens AC, Sklar CA, Kawashima T, Hudson MM, Meadows AT, et al. Chronic health conditions in adult survivors of childhood cancer. The New England journal of medicine. 2006;355(15):1572–82. doi: 10.1056/NEJMsa060185 17035650.

3. Gebauer J, Higham C, Langer T, Denzer C, Brabant G. Long-Term Endocrine and Metabolic Consequences of Cancer Treatment: A Systematic Review. Endocr Rev. 2019;40(3):711–67. Epub 2018/11/27. doi: 10.1210/er.2018-00092 30476004.

4. Bandak M, Jorgensen N, Juul A, Vogelius IR, Lauritsen J, Kier MG, et al. Testosterone deficiency in testicular cancer survivors—a systematic review and meta-analysis. Andrology. 2016;4(3):382–8. Epub 2016/03/25. doi: 10.1111/andr.12177 27009402.

5. Brydoy M, Fossa SD, Dahl O, Bjoro T. Gonadal dysfunction and fertility problems in cancer survivors. Acta Oncol. 2007;46(4):480–9. doi: 10.1080/02841860601166958 17497315.

6. Lehmann V, Chemaitilly W, Lu L, Green DM, Kutteh WH, Brinkman TM, et al. Gonadal Functioning and Perceptions of Infertility Risk Among Adult Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study. J Clin Oncol. 2019;37(11):893–902. Epub 2019/02/28. doi: 10.1200/JCO.18.00965 30811296.

7. Greenfield DM, Walters SJ, Coleman RE, Hancock BW, Eastell R, Davies HA, et al. Prevalence and consequences of androgen deficiency in young male cancer survivors in a controlled cross-sectional study. J Clin Endocrinol Metab. 2007;92(9):3476–82. doi: 10.1210/jc.2006-2744 17579201.

8. Greenfield DM, Walters SJ, Coleman RE, Hancock BW, Snowden JA, Shalet SM, et al. Quality of life, self-esteem, fatigue, and sexual function in young men after cancer: a controlled cross-sectional study. Cancer. 2010;116(6):1592–601. doi: 10.1002/cncr.24898 20186765.

9. Bhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(5):1715–44. Epub 2018/03/22. doi: 10.1210/jc.2018-00229 29562364.

10. Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA, et al. Effects of Testosterone Treatment in Older Men. N Engl J Med. 2016;374(7):611–24. Epub 2016/02/18. doi: 10.1056/NEJMoa1506119 26886521; PubMed Central PMCID: PMCPMC5209754.

11. Bhasin S, Woodhouse L, Casaburi R, Singh AB, Bhasin D, Berman N, et al. Testosterone dose-response relationships in healthy young men. Am J Physiol Endocrinol Metab. 2001;281(6):E1172–81. Epub 2001/11/10. doi: 10.1152/ajpendo.2001.281.6.E1172 11701431.

12. Woodhouse LJ, Gupta N, Bhasin M, Singh AB, Ross R, Phillips J, et al. Dose-dependent effects of testosterone on regional adipose tissue distribution in healthy young men. J Clin Endocrinol Metab. 2004;89(2):718–26. Epub 2004/02/07. doi: 10.1210/jc.2003-031492 14764787.

13. Wang C, Swerdloff RS, Iranmanesh A, Dobs A, Snyder PJ, Cunningham G, et al. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab. 2000;85(8):2839–53. Epub 2000/08/18. doi: 10.1210/jcem.85.8.6747 10946892.

14. Howell SJ, Radford JA, Adams JE, Smets EM, Warburton R, Shalet SM. Randomized placebo-controlled trial of testosterone replacement in men with mild Leydig cell insufficiency following cytotoxic chemotherapy. Clin Endocrinol (Oxf). 2001;55(3):315–24. Epub 2001/10/09. doi: 10.1046/j.1365-2265.2001.01297.x 11589674.

15. Garratt AM, Ruta DA, Abdalla MI, Buckingham JK, Russell IT. The SF36 health survey questionnaire: an outcome measure suitable for routine use within the NHS? BMJ. 1993;306(6890):1440–4. Epub 1993/05/29. doi: 10.1136/bmj.306.6890.1440 8518640; PubMed Central PMCID: PMCPMC1677883.

16. Webster K, Cella D, Yost K. The Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System: properties, applications, and interpretation. Health Qual Life Outcomes. 2003;1:79. Epub 2003/12/18. doi: 10.1186/1477-7525-1-79 14678568; PubMed Central PMCID: PMCPMC317391.

17. Derogatis LR. The Derogatis Interview for Sexual Functioning (DISF/DISF-SR): an introductory report. J Sex Marital Ther. 1997;23(4):291–304. Epub 1997/01/01. doi: 10.1080/00926239708403933 9427208.

18. Rosenberg M. Society and the adolescent self-image. Princeton, NJ: Princeton University Press; 1965.

19. Snyder PJ, Peachey H, Berlin JA, Hannoush P, Haddad G, Dlewati A, et al. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab. 2000;85(8):2670–7. doi: 10.1210/jcem.85.8.6731 10946864.

20. Brodsky IG, Balagopal P, Nair KS. Effects of testosterone replacement on muscle mass and muscle protein synthesis in hypogonadal men—a clinical research center study. J Clin Endocrinol Metab. 1996;81(10):3469–75. Epub 1996/10/01. doi: 10.1210/jcem.81.10.8855787 8855787.

21. Bhasin S, Storer TW, Berman N, Yarasheski KE, Clevenger B, Phillips J, et al. Testosterone replacement increases fat-free mass and muscle size in hypogonadal men. J Clin Endocrinol Metab. 1997;82(2):407–13. Epub 1997/02/01. doi: 10.1210/jcem.82.2.3733 9024227.

22. Behre HM, Tammela TL, Arver S, Tolra JR, Bonifacio V, Lamche M, et al. A randomized, double-blind, placebo-controlled trial of testosterone gel on body composition and health-related quality-of-life in men with hypogonadal to low-normal levels of serum testosterone and symptoms of androgen deficiency over 6 months with 12 months open-label follow-up. Aging Male. 2012;15(4):198–207. Epub 2012/07/28. doi: 10.3109/13685538.2012.699562 22834649.

23. Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, Snyder PJ, et al. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab. 2004;89(5):2085–98. Epub 2004/05/06. doi: 10.1210/jc.2003-032006 15126525.

24. Schoenfeld MJ, Shortridge E, Cui Z, Muram D. Medication adherence and treatment patterns for hypogonadal patients treated with topical testosterone therapy: a retrospective medical claims analysis. J Sex Med. 2013;10(5):1401–9. Epub 2013/03/08. doi: 10.1111/jsm.12114 23464534.

25. Aydogan U, Aydogdu A, Akbulut H, Sonmez A, Yuksel S, Basaran Y, et al. Increased frequency of anxiety, depression, quality of life and sexual life in young hypogonadotropic hypogonadal males and impacts of testosterone replacement therapy on these conditions. Endocr J. 2012;59(12):1099–105. doi: 10.1507/endocrj.ej12-0134 22972022.

26. Langham S, Maggi M, Schulman C, Quinton R, Uhl-Hochgraeber K. Health-related quality of life instruments in studies of adult men with testosterone deficiency syndrome: a critical assessment. J Sex Med. 2008;5(12):2842–52. Epub 2008/12/19. doi: 10.1111/j.1743-6109.2008.01015.x 19090941.

27. Mertens AC, Yasui Y, Neglia JP, Potter JD, Nesbit ME Jr., Ruccione K, et al. Late mortality experience in five-year survivors of childhood and adolescent cancer: the Childhood Cancer Survivor Study. J Clin Oncol. 2001;19(13):3163–72. doi: 10.1200/JCO.2001.19.13.3163 11432882.

28. Greenfield DM, Blewitt A, Coleman RE, Walsh JS, Snowden JA, Ross RJ, et al. Evaluation of adipocytokines and traditional cardiometabolic risk factors in young male cancer survivors: an age-matched control study. Clinical endocrinology. 2015. doi: 10.1111/cen.12869 26248973.

29. Neville KA, Cohn RJ, Steinbeck KS, Johnston K, Walker JL. Hyperinsulinemia, impaired glucose tolerance, and diabetes mellitus in survivors of childhood cancer: prevalence and risk factors. J Clin Endocrinol Metab. 2006;91(11):4401–7. doi: 10.1210/jc.2006-0128 16954158.

30. DeFilipp Z, Duarte RF, Snowden JA, Majhail NS, Greenfield DM, Miranda JL, et al. Metabolic syndrome and cardiovascular disease following hematopoietic cell transplantation: screening and preventive practice recommendations from CIBMTR and EBMT. Bone Marrow Transplant. 2017;52(2):173–82. Epub 2016/08/23. doi: 10.1038/bmt.2016.203 27548466; PubMed Central PMCID: PMCPMC5288134.

31. Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014;129(25 Suppl 2):S102–38. Epub 2013/11/14. doi: 10.1161/01.cir.0000437739.71477.ee 24222017; PubMed Central PMCID: PMCPMC5819889.

32. Haugnes HS, Wethal T, Aass N, Dahl O, Klepp O, Langberg CW, et al. Cardiovascular risk factors and morbidity in long-term survivors of testicular cancer: a 20-year follow-up study. J Clin Oncol. 2010;28(30):4649–57. Epub 2010/09/22. doi: 10.1200/JCO.2010.29.9362 20855830.

33. Saad F, Aversa A, Isidori AM, Zafalon L, Zitzmann M, Gooren L. Onset of effects of testosterone treatment and time span until maximum effects are achieved. Eur J Endocrinol. 2011;165(5):675–85. Epub 2011/07/15. doi: 10.1530/EJE-11-0221 21753068; PubMed Central PMCID: PMCPMC3188848.