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

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– 5], cardiovascular disease [ 6– 8] and metabolic syndrome [ 9– 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– 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.

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

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.

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.