Skip to main content
Download PDF

A randomized double-blind study of testosterone replacement therapy or placebo in testicular cancer survivors with mild Leydig cell insufficiency (Einstein-intervention)

BMC Cancer volume 17, Article number: 461 (2017) Cite this article

Abstract

Background

Elevated serum levels of luteinizing hormone and slightly decreased serum levels of testosterone (mild Leydig cell insufficiency) is a common hormonal disturbance in testicular cancer (TC) survivors. A number of studies have shown that low serum levels of testosterone is associated with low grade inflammation and increased risk of metabolic syndrome. However, so far, no studies have evaluated whether testosterone substitution improves metabolic dysfunction in TC survivors with mild Leydig cell insufficiency.

Methods/design

This is a single-center, randomized, double-blind, placebo-controlled study, designed to evaluate the effect of testosterone replacement therapy in TC survivors with mild Leydig cell insufficiency. Seventy subjects will be randomized to receive either testosterone replacement therapy or placebo. The subjects will be invited for an information meeting where informed consent will be obtained. Afterwards, a 52-weeks treatment period begins in which study participants will receive a daily dose of transdermal testosterone or placebo. Dose adjustment will be made three times during the initial 8 weeks of the study to a maximal daily dose of 40 mg of testosterone in the intervention arm. Evaluation of primary and secondary endpoints will be performed at baseline, 26 weeks post-randomization, at the end of treatment (52 weeks) and 3 months after completion of treatment (week 64).

Discussion

This study is the first to investigate the effect of testosterone substitution in testicular cancer survivors with mild Leydig cell insufficiency. If positive, it may change the clinical handling of testicular cancer survivors with borderline low levels of testosterone.

Trial registration

ClinicalTrials.gov: NCT02991209 (November 25, 2016).

Peer Review reports

Background

Testicular cancer (TC) is the most common solid tumour in men between 18 and 35 years of age in developed countries [1], and more than 95% of patients become long-term survivors [2]. In consequence, a wide range of studies have investigated the prevalence of late effects to TC treatment such as hormonal disturbances [3,4,5], cardiovascular disease [6,7,8] and metabolic syndrome [9,10,11,12]. The risk of cardiovascular disease is increased in TC patients treated with cisplatin-based chemotherapy when compared to the background population, and it has uniformly been reported that low serum levels of testosterone are associated with increased risk of metabolic syndrome. This has led to the hypothesis that decreased serum levels of testosterone in cancer survivors increase the risk of insulin resistance, metabolic syndrome and long-term risk of cardiovascular disease [13]. Subjective symptoms of testosterone deficiency are decreased libido, decreased level of energy, depressive symptoms, impaired cognitive function and decreased muscle strength while objective signs are decreased bone density, decreased lean body mass, abdominal obesity and anemia [14, 15]. It is well documented that testosterone replacement therapy improves these conditions in patients with manifest testosterone deficiency [16, 17] and numerous studies have demonstrated increased insulin sensitivity, decreased systemic inflammation and recovery of components of the metabolic syndrome [18,19,20]. However, a substantial proportion of TC survivors are in a compensated state with elevated luteinizing hormone (LH)-levels in combination with borderline low levels of testosterone (mild Leydig cell insufficiency) [21]. To our knowledge, only one study has examined the effects of testosterone replacement therapy in mild Leydig cell insufficiency [22]. This randomized, placebo-controlled study investigated the effect of 12 months of testosterone replacement therapy in 30 long-term survivors of haematological cancer and found a reduction of fatigue and a slight decrease in low density lipoprotein (LDL) cholesterol, and concluded that testosterone substitution should not be recommended in this condition. However, the limit for testosterone replacement therapy was total testosterone <20 mmol/L and LH > 8 IU/L and the effect on fasting blood glucose, insulin sensitivity and metabolic syndrome was not evaluated.

Thus, the purpose of the present study is to determine whether testosterone replacement therapy improves insulin sensitivity and thus potentially reduces the long-term risk of cardiovascular disease in TC survivors with mild Leydig cell insufficiency after TC treatment.

Methods/design

Study subjects

Seventy TC survivors with no relapse >1 year since treatment will be included in the study. The main inclusion criteria are serum levels of LH > 2 standard deviations (SD) above the age-adjusted mean value and serum levels of free testosterone between 2 SD below the age-adjusted mean value and the age-adjusted mean value. Further inclusion and exclusion criteria are presented in Table 1.

Table 1 Eligibility Criteria
Full size table

Recruitment and informed consent

The study flow is presented in Fig. 1. Potential study subjects will be recruited by clinicians during 5-years follow-up after treatment for TC at the outpatient clinic of Department of Clinical Oncology at Copenhagen University Hospital, Rigshospitalet. Interested patients will be contacted by the study coordinator, who will provide oral and written information about the study. An informed consent form will be signed, when there is a mutual understanding that the subject has understood the information given and still wants to participate. Afterwards, an appointment for screening will be made.

Fig. 1
figure 1

Study flow diagram

Full size image

Randomization and procedures for breakage of randomization code

The 70 study participants will be randomized 1:1 to active treatment or placebo. Randomization will be done by a web-based randomization tool (http://www.randomization.com). Each subject will be assigned a specific and unique randomization number. The randomization code will be broken for a subject if a suspected adverse event is judged by the investigators, as serious as it will influence future treatment. The randomization code can be broken at any time during the study period.

Blinding

Study participants and primary investigators are blinded. An unblinded investigator will evaluate safety issues.

Intervention

If a subject meets the inclusion criteria, reviewed at the screening and after the baseline investigations, randomization will take place and the study participant will be allocated to treatment with testosterone replacement therapy or placebo. He will initiate treatment the following day in the morning.

Study arm 1: Testosterone (Tostran 2% gel).

Study participants allocated to active treatment will receive 12 months daily treatment with Tostran 2% applied transdermally. Dose adjustment will take place three times during the initial 8 weeks to a maximal daily dose of 40 mg (four depressions of the piston) (Table 2).

Table 2 Dose adjustments and dose modifications due to safety issues
Full size table

Study arm 2: Placebo.

Study participants allocated to placebo will receive 12 months daily treatment with placebo. Identical dose adjustment will take place during the initial 8 weeks to four depressions of the piston (Table 2).

The summary of product characteristics of Tostran 2% can be seen at (http://www.medicines.org.uk/emc/medicine/19702). Placebo contains the same substances as Tostran 2% except for testosterone.

Tostran 2% and placebo will be supplied in an identical container labelled with a unique number. Each container has a piston and a depression of the piston delivers 0.5 g of gel which is equivalent to 10 mg of testosterone in the intervention group.

Dose modifications

Dose adjustment during the initial 8 weeks and criteria for dose modifications due to safety issues are shown in Table 2. If dose modification due to safety issues is needed, a study participant treated with placebo of the same age or age closest to the study participant who should be dose adjusted will be chosen for identical dose modification to keep the double-blinded study design. If more than one placebo-treated patient is at the same age, the subject with a BMI closest to the study participant who should be dose-adjusted will be chosen for identical dose modification.

Planned inclusion

It is estimated that 70 study participants will be included by the end of 2018.

Measurements

The schedule for data assessment is presented in Table 3 and the study endpoints are presented in Table 4.

Table 3 Data Assessment Schedule
Full size table
Table 4 Study Endpoints
Full size table

A human chorionic gonadotropin (hCG) stimulation test will be done at the screening visit in order to evaluate the residual capacity of the remaining testicle in the included study participants: After blood sampling, where serum testosterone is analysed, 5000 IU of hCG is injected intramuscularly. Blood samples are drawn 72 h after the administration of hCG for evaluation of serum testosterone.

Study endpoints will be evaluated at baseline (before randomization), 26 weeks post-randomization, 52 weeks post-randomization (last dose) and 64 weeks post-randomization (12 weeks after last dose). Participants will arrive at the hospital after an overnight fast (minimum 8 h) at visits where study endpoints will be evaluated.

Primary outcome

The primary endpoint is insulin sensitivity expressed as the 2 h change in blood glucose (∆2 h glucose) evaluated by oral glucose tolerance test: Fasting blood samples will be drawn where plasma glucose and insulin are analysed. Afterwards, at time zero, 75 g glucose will be administered orally after being dissolved in 250–300 ml water. Plasma glucose and insulin will be analysed again after 2 h.

Secondary outcomes

Evaluation of each component of metabolic syndrome (waist circumference, blood pressure, fasting plasma glucose, plasma HDL-cholesterol and plasma triglycerides) as well as presence of metabolic syndrome (≥3 components) will be assessed according to the International Diabetes Federation criteria [23]. Waist circumference and hip circumference will be measured according to guidelines from World Health Organization [24] and blood pressure will be determined twice with an automatic device after 5 min rest.

Plasma samples for analysis of inflammatory markers: tumor necrotic factor-alpha (TNF-alpha), interleukine (IL)-1β, IL-6 and IL-10 as well as adipocytokines (adiponectin and leptin) will be processed and stored at −80 C° for batch analysis after completion of the study. Inflammatory markers will be analysed by MesoScaleDiscovery multiplex (MesoScaleDiscovery, USA) while leptin will be analysed by immunoassay and adiponectin by radioimmunoassay.

Total plasma cholesterol, HDL-cholesterol, LDL-cholesterol, plasma glucose, haemoglobin A1c and plasma insulin will be measured using standard laboratory procedures. Homeostasis Model Assessment index will be calculated as described in [25].

Serum total testosterone and free testosterone will be analysed by liquid chromatography–mass spectrometry and LH will be analysed by time-resolved immunofluorometric assay (Delfia; Perkin Elmer, Turku, Finland),

Body composition and bone mineral density will be assessed by whole body Dual-energy X-ray absorptiometry (DXA-scan) performed on a Lunar Prodigy Advance Scanner (GE Healthcare, Madison, WI; software package Encore v. 16). Whole body bone mineral density (BMD) will be determined, as well as BMD of the lumbar spine and proximal femoral bone. Lean body mass, whole body fat percent, and visceral fat mass will be determined.

Anogenital distance will be measured in supine position with the legs abducted allowing the soles of the feet to meet as described in [26]. The anogenital distance will be measured at baseline and 52 months post-randomization using a digital caliper.

Patient reported outcomes will be assessed by standardized questionnaires: Quality of life (EORTC QLQ-30) [27], fatigue (Multiple Fatigue Inventory) [28], symptoms of testosterone deficiency and erectile dysfunction (International Index of Erectile Dysfunction) (IIEF-15) [29] and depression and anxiety (Hospital Anxiety and Depression Scale) (HADS) [30].

EORTC QLQ-30 consists of nine symptom scales, five function scales, and a global health/quality of life scale. A high score on the symptom scales indicates a high symptom burden while a high score on the function scales and global function scale indicates lower symptom burden. MFI-20 is covering five domains of fatigue: general fatigue, physical fatigue, reduced activity, reduced motivation and mental fatigue. A higher score on each of the five scales indicates more fatigue. HADS consists of two subscales covering anxiety and depression. A higher score on each scale indicates higher symptom burden. IIEF-15 examines the five main domains of male sexual function: Erectile function, orgasmic function, sexual desire, overall satisfaction and intercourse satisfaction. A lower score indicates higher symptom burden.

Additionally, study participants will be asked about medication, tobacco consumption, alcohol consumption and level of physical activity.

Adverse events

Presence of side effects according to common toxicity criteria version 4.0 (https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf) will be evaluated at each visit and documented in case report forms.

Sample size

It is expected that 30 study participants in each arm will complete the study to week 52. A power calculation has been conducted and with 30 study participants in each arm, there is 80% power to show a 0.5 mmol difference in ∆2 h glucose between baseline and 52 weeks between the two arms. The significance level is set at 5%.

Analytic plan

Changes in continuous outcomes between baseline and 52 weeks will be compared between the investigational group and placebo group with independent samples t-test. Changes in prevalence of metabolic syndrome components and metabolic syndrome between baseline and 52 weeks will be compared with chi-square test. Changes in patient reported outcomes and adverse events between baseline and 52 weeks will be compared with Mann–Whitney U-test. As an additional analysis outcomes in the intervention arm will be compared with independent samples t-test and chi-square test between study participants who had an adequate response to the hCG stimulation test performed at the screening visit and those who had and inadequate response.

Discussion

Testosterone substitution is currently advocated in men with evident biochemical testosterone deficiency measured on >1 occasion in concordance with clinical signs and symptoms of testosterone deficiency in the general population [31]. Mild Leydig cell insufficiency is a common condition in testicular cancer survivors, and it has not been clarified whether testosterone substitution is of potential benefit in this population. The results of the present study might have the potential to change the clinical handling of testicular cancer survivors with mild Leydig cell insufficiency in order to decrease the long-term risk of cardiovascular disease.

Recruitment of study participants began in November 2016. By the end of January 2017, approximately 60 potential study participants have received information about the study of which 22 have signed informed consent and been through screening examinations. The most common reason for not wanting to participate in the study after having received information has been that potential study participants found the study too time consuming. Fear of adverse effects to testosterone treatment has been the second most common reason for non-paticipation.

Ten of the 22 screened study participants have so far been randomized, four are in line for randomization while there have been eight screening failures.

As testosterone and LH show considerable day –to-day variation [32] screening failures would be expected. It should, however, be emphasized that all study participants who are undergoing screening examinations have experienced elevated serum LH levels in combination with borderline low serum testosterone at a previous point in time. Accordingly, inclusion in this study is based on at least two measurements of elevated LH and borderline low testosterone levels.

In conclusion, the results of this study will provide evidence for the clinical handling of TC survivors with mild Leydig cell insufficiency and potentially improve morbidity and quality of life in this subgroup of cancer survivors.

Abbreviations

Einstein:

Early INtervention with teSTostErone IN in testicular cancer survivors

HDL-cholesterol:

High density lipoprotein cholesterol

LDL-cholesterol:

Low density lipoprotein cholesterol

LH:

Luteinizing Hormone

SD:

Standard deviation

TC:

Testicular cancer

References

  1. Ferlay J, Shin H-R, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer [Internet]. 2010 [cited 2016 Oct 23]; 127:2893–917. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21351269.

  2. Verdecchia A, Francisci S, Brenner H, Gatta G, Micheli A, Mangone L, et al. Recent cancer survival in Europe: a 2000–02 period analysis of EUROCARE-4 data. Lancet Oncol. [Internet]. 2007 [cited 2016 Sep 8];8:784–96. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17714993.

  3. Nord C, Bjøro T, Ellingsen D, Mykletun A, Dahl O, Klepp O, et al. Gonadal hormones in long-term survivors 10 years after treatment for unilateral testicular cancer. Eur Urol. [Internet]. 2003 [cited 2013 Mar 27];44:322–8. Available from: http://dx.doi.org/10.1016/S0302-2838(03)00263-X.

  4. Wiechno P, Demkow T, Kubiak K, Sadowska M, Kamińska J. The quality of life and hormonal disturbances in testicular cancer survivors in Cisplatin era. Eur Urol. [Internet]. 2007 [cited 2016 Aug 18];52:1448–54. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17544206.

  5. Sprauten M, Brydøy M, Haugnes HS, Cvancarova M, Bjøro T, Bjerner J, et al. Longitudinal serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels in a population-based sample of long-term testicular cancer survivors. J Clin Oncol. [Internet]. 2014 [cited 2016 Apr 21];32:571–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24419125.

  6. van den Belt-Dusebout AW, Nuver J, de Wit R, Gietema JA, ten Bokkel Huinink WW, Rodrigus PTR, et al. Long-term risk of cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol. [Internet]. 2006 [cited 2017 Jan 3];24:467–75. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16421423.

  7. Meinardi MT, Gietema JA, van der Graaf WT, van Veldhuisen DJ, Runne MA, Sluiter WJ, et al. Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol. [Internet]. 2000 [cited 2013 Apr 8];18:1725–32. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10764433.

  8. Huddart RA, Norman A, Shahidi M, Horwich A, Coward D, Nicholls J, et al. Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol. [Internet]. 2003 [cited 2013 Apr 1];21:1513–23. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12697875.

  9. Haugnes HS, Aass N, Fosså SD, Dahl O, Klepp O, Wist EA, et al. Components of the metabolic syndrome in long-term survivors of testicular cancer. Ann Oncol. [Internet]. 2007 [cited 2013 Apr 4];18:241–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17060482.

  10. Nuver J, Smit AJ, Wolffenbuttel BHR, Sluiter WJ, Hoekstra HJ, Sleijfer DT, et al. The metabolic syndrome and disturbances in hormone levels in long-term survivors of disseminated testicular cancer. J Clin Oncol. [Internet]. 2005 [cited 2013 Apr 8];23:3718–25. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15738540.

  11. de Haas EC, Altena R, Boezen HM, Zwart N, Smit a J, Bakker SJL, et al. Early development of the metabolic syndrome after chemotherapy for testicular cancer. Ann Oncol. [Internet]. 2013;24:749–55. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23131388.

  12. Willemse PM, Burggraaf J, Hamdy N a T, Weijl NI, Vossen CY, van Wulften L, et al. Prevalence of the metabolic syndrome and cardiovascular disease risk in chemotherapy-treated testicular germ cell tumour survivors. Br J Cancer [Internet]. 2013;109:60–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23660945.

  13. de Haas EC, Oosting SF, Lefrandt JD, Wolffenbuttel BH, Sleijfer DT, Gietema JA. The metabolic syndrome in cancer survivors. Lancet Oncol. 2010;11:193–203.

    Article  PubMed  Google Scholar 

  14. Howell S, Shalet S. Testosterone deficiency and replacement. Horm. Res. [Internet]. 2001 [cited 2013 Apr 8];56 Suppl 1:86–92. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11786693.

  15. Zitzmann M, Nieschlag E. Hormone substitution in male hypogonadism. Mol Cell Endocrinol. [Internet]. 2000 [cited 2013 Apr 8];161:73–88. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10773395.

  16. 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;82:407–13.

    CAS  PubMed  Google Scholar 

  17. 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.

  18. Kapoor D, Clarke S, Stanworth R, Channer KS, Jones TH. The effect of testosterone replacement therapy on adipocytokines and C-reactive protein in hypogonadal men with type 2 diabetes. Eur J Endocrinol. 2007;156(5):595–602.

  19. Kalinchenko SY, Tishova YA, Mskhalaya GJ, Gooren LJG, Giltay EJ, Saad F. Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study. Clin Endocrinol. 2010;73:602–12.

    Article  CAS  Google Scholar 

  20. Malkin CJ, Pugh PJ, Jones RD, Kapoor D, Channer KS, Jones TH. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. J Clin Endocrinol Metab. 2004;89(7):3313–8.

  21. 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. 2011;47:2585–91.

    Article  CAS  PubMed  Google Scholar 

  22. Howell SJ, Radford JA, Adams JE, Smets EMA, Warburton R, Shalet SM. Randomized placebo-controlled trial of testosterone replacement in men with mild Leydig cell insufficiency following cytotoxic chemotherapy. Clin Endocrinol. 2001;55:315–24.

    Article  CAS  Google Scholar 

  23. Alberti KGMM, Zimmet P, Shaw J. The metabolic syndrome--a new worldwide definition. Lancet (London, England) [Internet]. 2015 [cited 2016 Aug 25];366:1059–62. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16182882.

  24. WHO. Waist Circumference and Waist–Hip Ratio: Report of a WHO Expert Consultation. Geneva: World Health; 2008. p. 8–11.

  25. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and $β$-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia [Internet]. 1985;28:412–9. Available from: http://dx.doi.org/10.1007/BF00280883.

  26. Eisenberg ML, Hsieh MH, Walters RC, Krasnow R, Lipshultz LI. The relationship between anogenital distance, fatherhood, and fertility in adult men. Plos One [Internet]. 2011 [cited 2017 Jan 13];6:e18973. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3092750&tool=pmcentrez&rendertype=abstract.

  27. Kaasa S, Bjordal K, Aaronson N, Moum T, Wist E, Hagen S, et al. The EORTC core quality of life questionnaire (QLQ-C30): validity and reliability when analysed with patients treated with palliative radiotherapy. Eur J Cancer [Internet]. 1995 [cited 2016 Mar 22];31A:2260–3. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8652253.

  28. Smets EM, Garssen B, Bonke B, De Haes JC. The multidimensional fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue. J Psychosom Res. [Internet]. 1995 [cited 2017 Jan 13];39:315–25. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7636775.

  29. Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A. The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology [Internet]. 1997 [cited 2017 Jan 13];49:822–30. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9187685.

  30. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. [Internet]. 1983 [cited 2017 Jan 13];67:361–70. Available from: http://www.ncbi.nlm.nih.gov/pubmed/6880820.

  31. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. [Internet]. 2010 [cited 2015 Feb 26];95:2536–59. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20525905.

  32. Brambilla DJ, O’Donnell AB, Matsumoto AM, McKinlay JB. Intraindividual variation in levels of serum testosterone and other reproductive and adrenal hormones in men. Clin Endocrinol. [Internet]. 2007 [cited 2017 Feb 6];67:853–62. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18052942.

Download references

Acknowledgements

No other contributions are considered.

Funding

Expenses will be paid by the Department of Oncology, Copenhagen University Hospital, Rigshospitalet. Kiowa Kirin International will cover expenses for Tostran and placebo. The Danish Cancer Society, The Danish Cancer Research Foundation and Rigshospitalet have supported the study.

Availability of data and materials

Once data has been obtained, analysed and published it will be made available.

Author information

Authors and Affiliations

  1. Department of Oncology, Copenhagen University Hospital, Rigshospitalet, 2100, Copenhagen, Denmark

    Mikkel Bandak, Jakob Lauritsen, Michael Kreiberg & Gedske Daugaard

  2. Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

    Niels Jørgensen & Anders Juul

  3. International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), University of Copenhagen, Copenhagen, Denmark

    Niels Jørgensen & Anders Juul

  4. Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

    Peter Sandor Oturai

  5. Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

    Jørn Wulff Helge

Authors
  1. Mikkel Bandak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Niels Jørgensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anders Juul
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jakob Lauritsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael Kreiberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Peter Sandor Oturai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jørn Wulff Helge
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gedske Daugaard
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MB, NJ, AJ, PS and GD developed the study concept and protocols. Primary investigator MB will implement the protocol with MK and NJ. MB drafted the manuscript; all authors contributed to revision and approval of the final manuscript.

Corresponding author

Correspondence to Mikkel Bandak.

Ethics declarations

Ethics approval and consent to participate

The study has been approved by the Regional Ethics committee for the Capital Region of Denmark (Protocol nr: H-15008901), the Danish Data Protection Agency (j.nr:2012–58-0004) and The Danish Health Authorities (EudraCT-number 2015–001452-30). The study will be monitored and quality assured by the Unit for Good Clinical Practice (GCP) at Copenhagen University Hospital.

All eligible participants will receive thorough oral and written information about the study. Study participants will be informed that they are free to drop out of the study at any time without consequence, and that their data may still be used in the analysis. All participants should provide a signed consent form before entering the study.

Consent for publication

All eligible participants will be explained that individual data will be pseudo-anonymized, and stored in a password-protected device only accessed by the researchers.

Competing interests

The authors declare that they have no competing interests.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bandak, M., Jørgensen, N., Juul, A. et al. A randomized double-blind study of testosterone replacement therapy or placebo in testicular cancer survivors with mild Leydig cell insufficiency (Einstein-intervention). BMC Cancer 17, 461 (2017). https://doi.org/10.1186/s12885-017-3456-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12885-017-3456-5

Keywords

BMC Cancer

ISSN: 1471-2407

Contact us