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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

Open AccessPublished:April 01, 2022DOI:https://doi.org/10.1016/j.clgc.2022.03.012

      Abstract

      Background

      Testicular cancer (TC) treatment leaves many patients with low levels of testosterone. While most TC patients with low testosterone (< - 2 SD) and hypogonadal symptoms will initiate testosterone replacement therapy (TRT), the role of TRT in patients with mild Leydig cell insufficiency, defined as elevated luteinizing hormone in combination with borderline low testosterone, is unknown. To clarify if TRT improves symptoms of depression and anxiety, sexual function, fatigue, and quality of life in TC survivors with mild Leydig cell insufficiency.

      Materials and Methods

      In total, 69 men aged between 18 and 65 years with mild Leydig cell insufficiency after TC treatment were randomized 1:1 to 12 months daily transdermal testosterone (maximum dose 40 mg/daily) vs. placebo. Patient reported anxiety, depression, sexual function, fatigue, and overall quality of life were assessed at baseline, after 6- and 12 months treatment, and 3 months post-treatment using validated questionnaires.

      Results

      After 12 months of treatment, median luteinizing hormone and median free testosterone were normalized in the testosterone group. Compared to placebo, TRT was not associated with statistically significant improvement of symptoms of anxiety and depression, sexual function, fatigue, and overall quality of life. Testosterone replacement therapy did not improve anxiety, depression, sexual function, fatigue, or overall quality of life in patients with mild Leydig cell insufficiency compared to placebo.

      Conclusion

      Routine TRT in TC survivors with mild Leydig cell insufficiency to improve sexual function and quality of life cannot be generally recommended. The findings should preferably be validated in a larger cohort.

      Keywords

      Introduction

      Testicular cancer (TC) mainly affects young men between 14 and 44 years of age
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      and the majority of patients become long-term survivors.
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      As unilateral orchiectomy is an integral part of treatment, the remaining testicle must compensate for loss of testosterone production. Around 5% to 10% of TC survivors develop testosterone deficiency after treatment with the need of testosterone replacement therapy (TRT).
      • Nord C
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      Gonadal Hormones in Long-Term Survivors 10 Years after Treatment for Unilateral Testicular Cancer.
      ,
      • Bandak M
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      Sexual function in a nationwide cohort of 2,260 survivors of testicular cancer after 17 years of followup.
      Furthermore, 20% to 30% will develop mild Leydig cell insufficiency which is defined as a compensated state characterized by elevated luteinizing hormone (LH) in combination with testosterone in the lower normal range.
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      Testosterone deficiency in testicular cancer survivors - a systematic review and meta-analysis.
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      The quality of life and hormonal disturbances in testicular cancer survivors in Cisplatin era.
      Testosterone replacement therapy is only recommended in patients with symptomatic testosterone deficiency.
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      Testosterone therapy in men with androgen deficiency syndromes: An endocrine society clinical practice guideline.
      In cancer-free populations, testosterone deficiency defined as total testosterone below the normal range is associated with higher incidence of fatigue,
      • Wu FCW
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      • et al.
      Identification of Late-Onset Hypogonadism in Middle-Aged and Elderly Men.
      depression,
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      and impaired sexual function,
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      and TRT has a positive effect on these conditions.
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      • 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.
      ,
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      Therapeutics and clinical risk management the benefits and risks of testosterone replacement therapy: a review.
      It remains unclear if TRT has a similar effect in TC survivors with mild Leydig cell insufficiency.
      In a cross-sectional study of 147 TC survivors, there was no statistically significant differences in quality of life, fatigue, or sexual function between patients with mild Leydig cell insufficiency and normal Leydig cell function.
      • Skøtt JW
      • Lauritsen J
      • Kreiberg M
      • Daugaard G
      • Bandak M.
      Quality of Life in Long-Term Testicular Cancer Survivors With Compensated Leydig Cell Dysfunction.
      However, patients with mild Leydig cell insufficiency more often had symptoms of depression (9% vs. 2%), decreased sexual desire (29% vs. 22%) and decreased overall satisfaction with sexual life (36% vs. 28%), indicating a higher symptom burden.
      • Skøtt JW
      • Lauritsen J
      • Kreiberg M
      • Daugaard G
      • Bandak M.
      Quality of Life in Long-Term Testicular Cancer Survivors With Compensated Leydig Cell Dysfunction.
      In another cross-sectional study of 680 TC survivors, elevated LH was statistically significantly associated with worries regarding fathering a child and less sexual activity.
      • Huddart RA
      • Norman A
      • Moynihan C
      • et al.
      Fertility, gonadal and sexual function in survivors of testicular cancer.
      In the present randomized double-blind study (NCT02991209), the effect of 12 months TRT in TC survivors with mild Leydig cell insufficiency was evaluated.
      • 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).
      The primary aim was to evaluate the effect on metabolic health, which has been reported in a previous publication.
      • Kreiberg M
      • Jørgensen N
      • Juul A
      • et al.
      A randomised double-blind study of testosterone replacement therapy or placebo in testicular cancer survivors with mild Leydig cell insufficiency. Accepted at.
      Here, we present the findings on patient reported anxiety and depression, overall quality of life, fatigue, and sexual function.

      Materials and Methods

      This was a single-center, double-blind, randomized, controlled clinical study, conducted at Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark between October 2016, and June 2019. The study protocol with a detailed description of study design has been published.
      • 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).
      The primary endpoint and related secondary outcomes assessing insulin sensitivity, metabolic health, body composition, and safety have been reported in a previous publication.
      • Kreiberg M
      • Jørgensen N
      • Juul A
      • et al.
      A randomised double-blind study of testosterone replacement therapy or placebo in testicular cancer survivors with mild Leydig cell insufficiency. Accepted at.

      Patients

      Men between 18 and 65 years who had undergone treatment for unilateral testicular cancer (orchiectomy, bleomycin, etoposide, cisplatin, abdominal radiotherapy) (Table 1) with no signs of relapse >1 year after last treatment and with presence of mild Leydig cell insufficiency, defined as serum levels of LH higher than 2 SD above the age-adjusted mean, in combination with calculated free testosterone levels above minus 2 SD and below the age-adjusted mean, were eligible for inclusion. Age-adjusted reference values for LH and free testosterone were calculated from healthy men as previously described.
      • Rasmussen SL
      • Torp-Pedersen C
      • Borch-Johnsen K
      • Ibsen H.
      Normal values for ambulatory blood pressure and differences between casual blood pressure and ambulatory blood pressure: results from a Danish population survey.
      ,
      • Gyllenborg J
      • Rasmussen SL
      • Borch-Johnsen K
      • et al.
      Cardiovascular risk factors in men: The role of gonadal steroids and sex hormone-binding globulin.
      Main exclusion criteria were paternity wish at the time of inclusion, TRT within the last 6 months, contraindications to testosterone treatment and diabetes. Patients were included regardless of symptoms of sexual dysfunction, fatigue, or impaired quality of life. Additional in- and exclusion criteria can be found in the study protocol.
      • 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).
      Table 1Baseline Characteristics in a 1:1 Randomized Trial of 12 Months Testosterone Replacement Therapy in 69 Testicular Cancer Survivors With Mild Leydig Cell Insufficiency
      Testosterone (N = 35)Placebo (N = 34)
      Age diagnosis, y
      Median (interquartile range (IQR))30 (25-38)33 (26-40)
      Age study inclusion, y
      Median (IQR)42 (35-47)44 (37-49)
      Time since diagnosis, y
      Median (IQR)5 (3-10)5 (3-13)
      Treatment, N (%)
      Orchiectomy only10 (29)21 (62)
      Chemotherapy13 (37)8 (24)
      Radiotherapy6 (17)2 (6)
      Chemotherapy and radiotherapy4 (11)2 (6)
      Orchiectomy and radiotherapy of contralateral testicle2 (6)1 (3)
      Luteinizing hormone, IU/L
      Median (IQR)8 (5-9)7.7 (6-10)
      Total testosterone, nmol/L
      Median (IQR)17.6 (15-20.1)15 (13.3-18.1)
      Free testosterone, pmol/L
      Median (IQR)330.5 (272-392)321.5 (268-378)
      Body mass index, kg/m2
      Median (IQR)24.8 (23.3-27.6)27.0 (24.0-28.6)
      Smoking status, N (%)
      Never13 (38)13 (38)
      Former8 (24)9 (26)
      Current13 (38)12 (35)
      Alcohol consumption units pr wk, N (%)
      Never6 (18)6 (18)
      <713 (38)16 (47)
      7-1410 (29)9 (26)
      14-213 (9)3 (9)
      >212 (6)0 (0)
      Due to slower recruitment than anticipated, a protocol amendment was decided on an investigator meeting, which was approved and implemented on November 10, 2017. The amendment allowed inclusion of patients with serum free testosterone below the age-adjusted upper limit of normal (+2 SD) and above -3 SD from the age-adjusted mean in combination with serum LH above +1 SD.

      Randomization

      Patients were randomized 1:1 in blocks of 10 to receive testosterone or placebo using a web-based randomization tool (http://www.randomization.com). Each patient was given a unique randomization number. The number could be unblinded at any time, if the patient was suspected to experience any serious adverse event.

      Intervention

      Testosterone and placebo were supplied in identical canisters with a unique identification number containing 60 grams of gel with a pumping mechanism delivering a fixed amount of gel which was applied transdermal every day. Placebo gel was an identical formulation without containing the active ingredient testosterone. Dose adjustments took place 3 times during the initial 8 weeks to a maximal daily dose of 40 mg (4 depressions on the pumping mechanism) which was considered sufficient to normalize testosterone. Dose reductions took place according to predefined safety criteria.
      • 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).

      Outcomes

      Outcomes were evaluated before initiation of treatment, after 6-months, 12-months and 3 months post-treatment (15 months) using validated questionnaires:
      Symptoms of anxiety and depression were assessed with the Hospital Anxiety and Depression Scale questionnaire (HADS),
      • Snaith RP.
      The hospital anxiety and depression scale.
      which consists of 2 separate subscales with 7 items assessing symptoms of anxiety and 7 items assessing symptoms of depression. Each item is answered on a 4-point (0-3) response category. The score ranges from 0 to 21 on each subscale with a score >7 considered abnormal.
      • Zigmond AS
      • Snaith RP.
      The hospital anxiety and depression scale.
      Overall quality of life was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30).
      • Aaronson NK
      • Ahmedzai S
      • Bergman B
      • et al.
      The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology.
      We only evaluated the global health and overall quality of life scales (C29 and C30). The score of each scale is transformed to a linear 0 to 100 score, with a lower score indicating a lower self-perceived quality of life.
      • Fayers P.M.
      • et al.
      EORTC QLQ-C30 Scoring Manual The EORTC QLQ-C30 Introduction.
      Sexual function was assessed with the International Index of Erectile Function questionnaire (IIEF-15).
      • 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.
      It is composed of 15 items assessing 5 domains of male sexual function: Erectile function (0-30), orgasmic function (0-10), sexual desire (0-10), intercourse satisfaction (0-15), and overall satisfaction (0-10). A lower score on each of the 5 subscales indicate a higher symptom burden.
      • Bushmakin AG
      • Cappelleri JC
      • Symonds T
      • Stecher VJ.
      Further understanding of the international index of erectile function at 15+ years: confirmatory factor analysis and multidimensional scaling.
      Fatigue was assessed with the Multidimensional Fatigue Inventory (MFI-20).
      • Smets EMA
      • Garssen B
      • Bonke B
      • de Haes J.
      Pergamon FATIGUE INVENTORY (MFI) PSYCHOMETRIC QUALITIES OF AN INSTRUMENT TO.
      It covers 5 domains of fatigue in corresponding subscales: General fatigue, physical fatigue, mental fatigue, reduced motivation, and reduced activity. There are 4 items on each domain, with scores from 1 to 5 with a total subscale score from 4 to 20 with a higher score indicating a higher symptom burden.

      Hormone Analyses

      Serum concentrations of LH were measured by time-resolved immunofluorometric assay (Delfia; Perkin Elmer, Turku, Finland) with intra-assay and inter-assay coefficient of variation (CV) <5% and detection limits of 0.05 IU/L. Testosterone concentrations were quantified using an isotope-dilution TurboFlow-LC–MS/MS method as previously published.
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      • Frederiksen H
      • Johannsen TH
      • Andersson AM
      • Juul A.
      Isotope-dilution TurboFlow-LC-MS/MS method for simultaneous quantification of ten steroid metabolites in serum.
      Free testosterone was calculated as described by Vermeulen et al.
      • Vermeulen A
      • Verdonck L
      • Kaufman JM.
      A critical evaluation of simple methods for the estimation of free testosterone in serum.
      assuming a fixed albumin of 43 g/L. Laboratory analyses were performed in the morning between 6.30 am 11.00 am.

      Statistical Analysis

      The primary outcome in NCT02991209 was insulin sensitivity after 12 months of testosterone substitution evaluated by a 2-hour Oral Glucose Tolerance Test.
      • 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).
      To accommodate a statistical power of 80% and a significance level of 5%, a total of 30 patients in each group should complete 12 months of study. We aimed to include 70 patients, leaving room for a maximum drop out of 10 patients.
      Linear mixed effects models were used to compare longitudinal changes in primary and secondary outcomes between groups over time, according to the intention-to-treat principles as described by Twisk et al.,
      • Twisk JWR
      • Bosman L
      • Hoekstra T
      • Rijnhart J
      • Welten M
      Heymans M. Different ways to estimate treatment effects in randomised controlled trials.
      with adjustment for potential baseline differences. The models included fixed effects for visit number, treatment effects for visits at months 6, 12, and 15 and a random effect for each patient and for the correlation between visits for within patients we used an unstructured correlation structure, i.e., not assuming a specific correlation structure.
      Continuous variables are presented as median with interquartile range (IQR), while categorical variables are presented as number and percentages.
      All statistical analyses were done in R version 3.6.2 using package nlme by R Core Team (2019). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria.
      The study was monitored by the Unit for Good Clinical Practice (GCP) at the Copenhagen University Hospital, Bispebjerg, Denmark.
      The study was registered at www.clinicaltrials.gov (NCT02991209).

      Results

      Between November 2016 and March 2018, 140 patients were screened for eligibility and 69 patients were randomized to receive testosterone (n = 35) or placebo (n = 34). A consort diagram of included patients has been included in a previous publication.
      • Kreiberg M
      • Jørgensen N
      • Juul A
      • et al.
      A randomised double-blind study of testosterone replacement therapy or placebo in testicular cancer survivors with mild Leydig cell insufficiency. Accepted at.
      Median LH and free testosterone were comparable between the groups at baseline (Table 1). More patients in the placebo group were treated with orchiectomy alone (n = 21 vs. n = 10), while BMI, tobacco consumption, and alcohol consumption were comparable between the groups.
      After dose titration, 26 patients were treated with 40 mg daily testosterone, while 3 patients were treated with 30 mg, 5 patients with 20 mg and 1 patient with 10 mg/day.
      After 12 months of treatment, median LH was 4.2 IU/L (IQR: 3.5-6.7) and median free testosterone 541.9 pmol/L (IQR: 410.0-714.7) in the testosterone group, while median LH was 7.6 IU/L (IQR: 6.3-8.7) and median free testosterone 317.4 pmol/L (IQR: 273.8-347.2) in the placebo group.
      Patient reported quality of life and symptoms of sexual dysfunction at baseline are presented in Table 2.
      Table 2Baseline Scores on Quality of life and Sexual Function Evaluated With Questionnaires in a 1:1 Randomized Trial of 12 Months Testosterone Replacement Therapy in 69 Testicular Cancer Survivors With Mild Leydig Cell Insufficiency
      Patient reported outcomesTestosterone(n=35)Placebo(n = 34)
      HADS Anxiety (range: 0-21)

      Median (IQR)
      6 (4-10.5)5 (3-8)
      HADS Depression (range: 0-21)

      Median (IQR)
      4 (3-6.5)3 (2-6)
      EORTC-QLQ-C30 Global health (range: 1-100)

      Mean (SD)


      72.9 (19.4)


      71.6 (14.5)
      EORTC-QLQ-C30 Overall quality of life (range: 1-100)

      Mean (SD)


      69.5 (22)


      73.5 (17.5)
      IIEF Erectile function (range: 0-30)

      Median (IQR)


      28 (23.5-30)


      29 (26.3-30)
      IIEF Orgasmic function (range: 0-10)

      Median (IQR)


      10 (8-10)


      10 (8.5-10)
      IIEF Sexual desire (range: 0-10)

      Median (IQR)


      7 (5.5-8)


      6 (5.5-8)
      IIEF Intercourse satisfaction (range: 0-15)

      Median (IQR)


      10 (9-12)


      11 (9-12)
      IIEF Overall satisfaction (range: 0-10)

      Median (IQR)


      8 (6-8)


      7 (7-8)
      MFI General fatigue (range: 4-20)

      Median (Q1-Q3)


      12 (9-13)


      11 (10-13)
      MFI Physical fatigue (range: 4-20)
      Median (IQR)11 (7.5-12)9 (6.3-10.8)
      MFI Reduced activity (range: 4-20)

      Median (IQR)


      8 (5-11.5)


      9 (6-10)
      MFI Reduced motivation (range: 4-20)

      Median (IQR)


      7 (5-10.5)


      8 (6.3-10)
      MFI Mental fatigue (range: 4-20)

      Median (IQR)


      10 (8-13)


      8 (6-11)
      Abbreviations: HADS = Hospital Anxiety and Depression Scale questionnaire; EORTC-QLQ-C30 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; IIEF-15 = International Index of Erectile Function questionnaire, MFI-20 = Multidimensional Fatigue Inventory

      Changes in Patient Reported Symptoms During and After TRT

      Compared to placebo, TRT was not associated with statistically significant improvement of anxiety or depression, overall quality of life, sexual function, or fatigue after 12 months of treatment (Figure 1-3, Table 3). Similarly, there were no statistically significant differences in the investigated outcomes 3 months post treatment, except for “reduced activity” assessed with MFI-20 where the testosterone group had a small but statistically significant higher symptom burden (1.70 95% CI [0.21, 3.20]) compared to placebo (Figure 3C, Table 3).
      Figure 1
      Figure 1Mean scores with 95% confidence intervals of Hospital Anxiety and Depression Scale (HADS) Anxiety (A), HADS-Depression (B) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30), C29 Global Health (C) and C30 Overall Quality of Life, (D) at baseline, 6 months, 12 months, and 3 months post-treatment (15 months). Blue lines represent mean values for patients treated with testosterone and orange lines represent placebo.
      Table 3Difference in Outcomes Between Patients Treated With Testosterone and Placebo After (6 Months, 12 Months) and 3 Months Post-Treatment (15 Months). The Difference in Changes Between Groups Are Reported With 95% Confidence Intervals and was Estimated With a Linear Mixed Effects Model.
      6 mo12 mo15 mo
      EstimateCIEstimateCIEstimateCI
      HADS
      Anxiety-0.09-0.33, 0.160.18-0.11, 0.47-0.05-0.33, 0.23
      Depression-0.06-0.34, 0.230.12-0.22, 0.450.09-0.2, 0.38
      EORTC
      Global Health-0.71-6.69, 8.11-1.69-9.98, 6.62.28-5.42, 9.98
      Overall quality of life3.59-4.78, 11.97-0.83-9.4, 7.743.25-5.13, 11.62
      IIEF
      Erectile function0.56-1.23, 2.350.35-1.51, 2.22-0.69-3.39, 2.02
      Orgasmic function0.16-0.65, 0.96-0.69-1.56, 0.18-0.46-1.25, 0.34
      Sexual desire-0.28-1.07, 0.51-0.38-1.21, 0.44-0.35-1.20, 0.50
      Intercourse satisfaction0.24-0.92, 1.41-0.12-1.38, 1.14-0.31-1.92, 1.30
      Overall satisfaction0.09-0.67, 0.85-0.53-1.17, 0.11-0.08-0.95, 0.79
      MFI
      General fatigue0.29-1.40, 1.981.01-0.53, 2.560.02-1.44, 1.48
      Physical fatigue-0.63-2.10, 0.85-0.15-1.61, 1.310.03-1.52, 1.58
      Reduced activity-0.01-1.53, 1.510.90-0.72, 2.521.700.21, 3.20
      Reduced motivation-0.89-2.21, 0.430.92-0.37, 2.210.54-0.72, 1.79
      Mental fatigue-0.27-1.51, 0.960.55-0.91, 2.01-0.49-1.72, 0.73
      Abbreviations: HADS = Hospital Anxiety and Depression Scale questionnaire; EORTC-QLQ-C30 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; IIEF-15 = International Index of Erectile Function questionnaire; MFI-20 = Multidimensional Fatigue Inventory.
      To account for a possible imbalance in treatment modalities between the groups, we conducted an analysis adjusting for treatment modality (orchiectomy vs. other treatment modalities). This did not change any of the investigated outcomes, data not shown.
      Although it was not an aim of the study, we finally evaluated if patients in the placebo group reported improvement in quality of life during the intervention. We found, a statistically significant improvement in sexual desire in the placebo group after 6 months (0.99, 95% CI 0.40-1.59) and 12 months (0.79, 95% CI 0.22-1.36), in intercourse satisfaction after 6 months (1.06, 95% CI 0.19-1.93) and in overall sexual function after 12 months (0.68, 95% CI 0.21-1.14) (Figure 2 C-E).
      Figure 2
      Figure 2Mean scores with 95% confidence intervals of International Index of Erectile Function questionnaire (IIEF-15), Erectile function (A), Orgasmic function (B), Sexual desire (C) and Intercourse satisfaction (D), Overall satisfaction (E) at baseline, 6 months, 12 months, and 3 months post treatment (15 months). Blue lines represent mean values for patients treated with testosterone and orange lines represent placebo.
      Similarly, in the placebo group, a statistically significant reduction in general fatigue was observed after 6 months (-1.60, 95% CI -2.93; -0.27), 12 months (-1.81, 95% CI -2.91; -0.71) and 3 months post-treatment (-1.07, 95% CI -2.09; -0.04) and in mental fatigue after 6 months (-1.14, 95% CI -2.07; -0.21) and 3 months post-treatment (-1.02, 95% CI, -1.89; -0.15) (Figure 3 A-E).
      Figure 3
      Figure 3Mean scores with 95% confidence intervals of Multidimensional Fatigue Inventory (MFI-20), General fatigue (A), Physical fatigue (B), Reduced activity (C), Reduced motivation (D), Mental fatigue (E) at baseline, 6 months, 12 months, and 3 months post treatment (15 months). Blue lines represent mean values for patients treated with testosterone and orange lines represent placebo.

      Discussion

      In this randomized double-blind study of TC survivors with mild Leydig cell insufficiency, 12 months of TRT was not associated with improvement in self-reported sexual function or quality of life compared to placebo.
      In the intervention group, free testosterone increased to high-normal levels at 12 months which should be sufficient to observe an effect on sexual function and quality of life
      • Brock G
      • Heiselman D
      • Maggi M
      • et al.
      Effect of testosterone solution 2% on testosterone concentration, sex drive and energy in hypogonadal men: results of a placebo controlled study.
      and therefore it seems unlikely that the negative findings were caused by a too low testosterone dose or a too short treatment duration. However, there was a very modest symptom burden at baseline on some outcomes, particularly erectile function, and orgasmic function where the scores were comparable to healthy controls,
      • 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.
      and the overall quality of life was high in both groups leaving little room for improvement with TRT.
      In The European Male Aging Study (EMAS), general, sexual, physical, and psychological health were evaluated with validated questionnaires in association with testosterone levels in a random population sample of 3369 men between the ages of 40 and 79 years.
      • Wu FCW
      • Tajar A
      • Beynon JM
      • et al.
      Identification of Late-Onset Hypogonadism in Middle-Aged and Elderly Men.
      In general, only weak associations between testosterone levels and these conditions were reported, and free testosterone had to be < 280 pmol/L to observe a statistically significant increase in erectile dysfunction and <160 pmol/L to observe a statistically significantly increased risk of decreased frequency of sexual thoughts, fatigue, and sadness. At the same time, symptoms of sexual dysfunction were present in >20% of patients with free testosterone > 160 pmol/L, while fatigue and sadness were present in around 10% of patients with free testosterone > 280 pmol/L emphasizing the multifactorial etiology of these conditions. In the present study, median free testosterone among the included patients was 325 pmol/L, which is considerably higher than the cut-off values for symptoms from EMAS, which might partially explain the low symptom burden at baseline.
      Our findings are in line with that reported by Walsh et al.
      • Walsh JS
      • Marshall H
      • Smith IL
      • et al.
      Testosterone replacement in young male cancer survivors: a 6-month double-blind randomised placebo-controlled trial.
      in a similarly designed study. They evaluated the effect of 6-months TRT in a double-blind randomized trial of 136 male survivors of testicular cancer (n = 120), lymphoma (n = 14) and leukemia (n = 2) with borderline low levels of total testosterone (7.0-12.0 nmol/L). In total, 50 of 68 patients in the intervention group were treated with 60 mg daily testosterone or more, which is higher than in the present study, where the maximum testosterone dose was 40 mg/day. In accordance with the present findings, there was a low symptom burden at baseline and testosterone substitution was not associated with improvement in any of these outcomes.
      Interestingly, in the placebo group, we observed a small but statistically significant improvement in sexual desire, intercourse satisfaction and overall sexual satisfaction as well as a reduction in general fatigue and mental fatigue. The improvement was around 1 point on both the IIEF-15 scale and MFI-20 scale and was equivalent to changes in the intervention arm. As the included patients were long-term cancer survivors where spontaneous improvement does not seem plausible, our findings are suggestive of a placebo effect. This finding underlines the importance of placebo control when evaluating the effect of testosterone substitution on sexual function and fatigue.

      Strengths and Limitations

      Strengths of the present study include the careful dose titration of testosterone, the 12 months treatment duration and the use of validated questionnaires to assess outcomes. We decided to use free testosterone rather than total testosterone as an inclusion criterion, as decreased free testosterone is less associated with obesity than decreased total testosterone due to the inverse relation between sexual hormone binding globulin and obesity.
      • Hautanen A.
      Synthesis and regulation of sex hormone-binding globulin in obesity.
      ,
      • Rees DA
      • Dayan CM.
      Commentary: testosterone and the metabolic syndrome: cause or consequence?.
      It is a limitation that patients had very few symptoms at baseline on many of the evaluated outcomes, indicating a ceiling effect with little room for improvement with TRT. Further limitations include the imbalance in treatment modalities between the 2 groups, despite randomization. However, adjusting for treatment modality did not change any outcomes. Finally, the inclusion criteria were modified during the study to allow inclusion of patients with lower LH and higher testosterone, which might have allowed inclusion of patients with a lower symptom burden and thus less potential for improvement. Due to the small sample size, we did not find it meaningful to perform a subgroup analysis of patients fulfilling the original inclusion criteria. Finally, it should be noted that the study was powered for the primary outcome and caution is needed when interpreting secondary outcomes.

      Conclusion

      TRT in TC survivors with mild Leydig cell insufficiency did not improve patient reported anxiety and depression, overall quality of life, sexual function or fatigue, and the findings do not support routine use of TRT in these patients. The statistical precision was low, however, and it is not possible to draw a firm conclusion.
      Future studies should evaluate testosterone substitution in TC patients with mild Leydig cell insufficiency in combination with evident symptoms of sexual dysfunction, fatigue, or impaired quality of life. In addition, the causes of sexual dysfunction and impaired quality of life in TC survivors should be further explored.

      Clinical Practice Points

      We identified one study which assigned 35 hematological cancer survivors with mild Leydig Cell insufficiency to 12 months testosterone replacement therapy (TRT) or placebo. The intervention did not result in significant changes in body composition, lipids or quality of life. We conducted a MEDLINE search of published study in English up to September 1, 2015, and we did not find other randomized studies which assessed TRT in cancer survivors.
      In this randomized double-blind study of TRT or placebo in 69 testicular cancer survivors with mild Leydig cell insufficiency, defined as elevated serum levels of Luteinizing Hormone (LH) in combination with borderline low serum levels of testosterone, the primary outcome was changes in metabolic health. In the present study we present the secondary outcomes of quality of life and sexual function. We successfully raised testosterone levels in the intervention group to high normal range. After 12-months treatment there was no statistically significant difference in quality of life and sexual function between patients treated with testosterone or placebo. This study adds to the limited knowledge of the clinical handling of cancer survivors with low testosterone in combination with elevated LH.
      In conclusion, 12 months TRT in testicular cancer survivors with mild Leydig Cell insufficiency did improve quality of life and sexual function and should not be standard treatment in these patients. Our findings should preferably be validated in a larger study.

      Other Information

      Trial Registration

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

      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.

      CRediT authorship contribution statement

      Emma Grunwald Højer: Investigation, Writing – original draft, Visualization. Michael Kreiberg: Investigation, Writing – review & editing. Christian Dehlendorff: Methodology, Formal analysis, Visualization. Niels Jørgensen: Conceptualization, Methodology, Writing – review & editing. Anders Juul: Conceptualization, Methodology, Writing – review & editing. Jakob Lauritsen: Writing – review & editing. Thomas Wagner: Writing – review & editing. Josephine Rosenvilde: Writing – review & editing. Gedske Daugaard: Conceptualization, Methodology, Writing – review & editing. Mikkel Bandak: Conceptualization, Investigation, Methodology, Writing – review & editing, Funding acquisition.

      Disclosure

      The authors declare that they have no competing interests.

      Acknowledgments

      The full trial protocol can be assessed at: https://www.ncbi.nlm.nih.gov/pubmed/28673265

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