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Effect of Testosterone Replacement Therapy on Quality of Life and Sexual Function in Testicular Cancer Survivors with Mild Leydig Cell Insufficiency: Results from a Randomized Double-Blind Trial - Beyond the Abstract

Testicular cancer (TC) is one of the most curable cancers nowadays, with a 5-year survival rate of 97,3% in Europe,1 but several long-term complications have been related to the treatment.2 Approximately 50% of patients have disease confined to the testicle and will be cured with unilateral orchiectomy alone, while the remaining 50% will need additional cisplatin-based chemotherapy or abdominal radiotherapy, because of disease spread.3


The pituitary gland excretes luteinizing hormone (LH) and follicle stimulating hormone (FSH) in response to gonadotropin releasing hormone (GnRH) from the hypothalamus. LH stimulates the production of testosterone from Leydig cells in the testicles.4

Post orchiectomy, a great proportion of TC survivors develop mild Leydig cell insufficiency, which means they are in a compensated state with elevated LH and borderline low levels of s-testosterone.5 Furthermore, the toxic effects of radiotherapy and chemotherapy will reduce the Leydig cell function and contribute to a reduction in testosterone production too,6 with the risk appearing to be highest in the most heavily treated patients.7

In non-cancerous populations, testosterone deficiency, defined as total testosterone below the normal range, is associated with a higher incidence of fatigue,8 depression,9 and impaired sexual function10  as well as several other illnesses.11-13 Testosterone replacement therapy (TRT) has shown a positive effect on these conditions.14,15 To our knowledge, only one other study has investigated this question16 why it’s still not clear if TRT has a similar effect in TC survivors with mild Leydig cell insufficiency.

This study is a randomized double blind clinical trial, investigating the effect of testosterone replacement therapy in 69 TC survivors over a 12-month period.

The primary aim was to evaluate the effect on metabolic health, which has been reported in a previous publication.17 In this article, we present the secondary findings on patient reported anxiety and depression, overall quality of life, fatigue, and sexual function among TC survivors with. There was no improvement in the patient reported outcomes, routine testosterone substitution in this patient group is not recommended, but the article contains recommendations for further investigation of this subject.

Written by: Emma Grunwald Højer, MD, Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

References:

  1. Verdecchia A, Francisci S, Brenner H, et al. Recent cancer survival in Europe: a 2000-02 period analysis of EUROCARE-4 data. Lancet Oncol. 2007;8(9):784-796. doi:10.1016/S1470-2045(07)70246-2
  2. Fung C, Fossa SD. Long-term Morbidity of Testicular Cancer Treatment. Published online 2015:420318.
  3. Krege S, Beyer J, Souchon R, et al. European Consensus Conference on Diagnosis and Treatment of Germ Cell Cancer: A Report of the Second Meeting of the European Germ Cell Cancer Consensus group (EGCCCG): Part I. Eur Urol. 2008;53(3):478-496. doi:10.1016/j.eururo.2007.12.024
  4. Oldenburg J. Hypogonadism and fertility issues following primary treatment for testicular cancer. Urol Oncol. 2015;33(9):407-412. doi:10.1016/j.urolonc.2015.01.014
  5. Bandak M, Aksglaede L, Juul A, Rørth M, Daugaard G. The pituitary-Leydig cell axis before and after orchiectomy in patients with stage I testicular cancer. Eur J cancer. 47(17):2585-2591. doi:10.1016/j.ejca.2011.05.026
  6. Pühse G, Secker A, Kemper S, Hertle L, Kliesch S. Testosterone deficiency in testicular germ-cell cancer patients is not influenced by oncological treatment. Int J Androl. 2011;34(5 PART 2):351-357. doi:10.1111/j.1365-2605.2010.01123.x
  7. Bandak M, Jørgensen N, Juul A, et al. Testosterone deficiency in testicular cancer survivors - a systematic review and meta-analysis. Andrology. 2016;4(3):382-388. doi:10.1111/andr.12177
  8. Mullhall, J. P., MD; Trost, L. W., MD; Branigan, R. E, MD; Kurtz, E. G., MD; Redmon, J. B., MD; Chiles, K. A., MD MSc; Lightner, D. J., MD; Miner, M. M., MD; Murad M. H. MD, MPH; Nelson C. J., PhD; Platz, E. A., ScD, MPH; Ramanathan, L. V., PhD; Lewis, R. M. AUA Guideline TRT. Am Urol Assoc Clin Guidel. 2018;(February).
  9. Zitzmann M. Testosterone and the brain. In: Aging Male. Vol 9. ; 2006:195-199. doi:10.1080/13685530601040679
  10. Nazareth I, Lewin J, King M. Sexual dysfunction after treatment for testicular cancer: a systematic review. J Psychosom Res. 2001;51(6):735-743.
  11. de Haas EC, Oosting SF, Lefrandt JD, Wolffenbuttel BHR, Sleijfer DT, Gietema JA. The metabolic syndrome in cancer survivors. Lancet Oncol. 2010;11(2):193-203. doi:10.1016/S1470-2045(09)70287-6
  12. Howell, S. J. Shalet S. Testosterone deficiency and replacement. Horm Res. 2001;56(17/OCT.):43.
  13. Zitzmann M, Nieschlag E. Hormone substitution in male hypogonadism. Mol Cell Endocrinol. 2000;161(1):73-88. doi:https://doi.org/10.1016/S0303-7207(99)00227-0
  14. Ponce OJ, Spencer-Bonilla G, Alvarez-Villalobos N, et al. The Efficacy and Adverse Events of Testosterone Replacement Therapy in Hypogonadal Men: A Systematic Review and Meta-Analysis of Randomized, Placebo-Controlled Trials. J Clin Endocrinol Metab. 2018;103(5):1745-1754. doi:10.1210/jc.2018-00404
  15. Bassil N, Alkaade S, Morley JE. Therapeutics and Clinical Risk Management The benefits and risks of testosterone replacement therapy: a review. Ther Clin Risk Manag. Published online 2009:5-427. www.dovepress.com
  16. Walsh JS, Marshall H, Smith IL, et al. Testosterone replacement in young male cancer survivors: A 6-month double-blind randomised placebo-controlled trial. PLoS Med. 2019;16(11):1-18. doi:10.1371/journal.pmed.1002960
  17. Michael Kreiberg, 1 Niels Jørgensen, 2, 3 Anders Juul, 2, 3 Jakob Lauritsen, 1 Peter Sandor Oturai, 4 Jørn Wulff Helge, 5 Jesper Frank Christensen, 6 Lise Aksglæde, 2 Tim Schauer, 6 Thomas Wagner, 1 Josephine Rosenvilde, 1 Christian Dehlendorff 7 Gedske Daugaard1 & Mikkel Bandak1. A randomized double-blind study of testosterone replacement therapy or placebo in testicular cancer survivors with mild Leydig cell insufficiency (Einstein-intervention). Published online 2021.

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