Testosterone therapy may reduce prostate cancer risk due to testosterone deficiency at a young age via stabilizing serum testosterone levels

Abstract

Objectives: To investigate whether testosterone replacement therapy (TRT) reduces prostate cancer (PCa) risk via stabilizing serum testosterone (T) levels beyond simply elevating serum T levels and whether TRT reduces PCa risk due to low serum T levels at a young age.

Methods: We analyzed data of 776 hypogonadal men from a urology center in Bremerhaven, Germany through 2004–2016 to investigate whether the TRT group has more stable T levels and whether TRT can reduce the risk of PCa due to low serum T levels at an early age. We derived an index, Maximum Decline of T Relative to Baseline (MDRB), to describe the magnitude of T declines and variations over time.

Results: We found the TRT group has more stable serum T levels (e.g. smaller drop-offs) during the follow-up period as compared to the non-TRT group, and the mean of MDRB is significantly higher in the untreated group (1.553 nmol/L VS 0.013 nmol/L; p-value < .001). TRT significantly reduces the risk of PCa associated with T deficiency at a young age (p-value = .00087).

Conclusions: TRT may reduce PCa risk via maintaining serum T levels within individual’s normal range; T surveillance may be needed for males who have low serum T levels at a young age to monitor abnormal variations of T levels and ensure timely treatment when necessary to reduce PCa risk.

Keywords:

• Prostate cancer
• testosterone replacement therapy
• testosterone deficiency
• long-term fluctuations of testosterone levels

Introduction

Prostate cancer (PCa) is the second most common cancer and the third leading cause of cancer death in American males [1]. As the main male hormone, testosterone (T) is crucial for prostate health. T declines gradually as men age, ∼0.11 to 0.12 nmol/L (3.2 to 3.5 ng/dL) per year [2] from middle to late adulthood. Abnormal age-related T declines, significant variations of T levels, and T deficiency (i.e. hypogonadism, a clinical syndrome consisting of a variety of symptoms along with low serum T levels [3] at a young age have been reported to be associated with increased risk of PCa and many metabolic abnormalities and urogenital diseases [4–6]. Our recent study shows among untreated hypogonadal males, those who did not develop PCa during the follow-up period were more likely to have stable T levels [5].

Testosterone replacement therapy (TRT) is a commonly used treatment for mitigation of the symptoms and metabolic sequelae of T deficiency, and recent studies have suggested the benefits of TRT in reducing PCa risk and severity, and prolonging survival of existing PCa cases [3,7–9]. More and more evidence has emerged that challenges the long-accepted theory that PCa is activated by androgen injections [10,11]. However, whether TRT reduces PCa risk via stabilizing serum T levels beyond simply elevating serum T levels to an individual’s normal range has not yet been investigated. In addition, whether TRT reduces PCa risk due to low serum T levels at a young age is currently unknown.

In this study, we analyzed data from a prospective cohort of 776 hypogonadal men from a urology center in Bremerhaven, Germany through 2004–2016 to achieve the following aims: (1) examine the association between dynamic patterns (e.g. age at T deficiency/significant T declines, variations) of T and risk of PCa among hypogonadal males; (2) investigate whether TRT group has more stable T levels; (3) investigate whether TRT can reduce the risk of PCa due to pronounced T drop-offs at young ages.

Methods and materials

Study population

We used de-identifiable data from a registry study in Germany. Seven hundred and seventy-six men were recruited from one urology center in Bremerhaven, Germany from 2004 to 2016, where they had sought medical consultation for various urological complaints including sexual dysfunction. Hypogonadism diagnosis was confirmed if they had total T level ≤ 12.1 nmol/L (∼350 ng/dL) and symptoms as assessed by the Aging Males’ Symptoms scale (AMS). We have chosen the threshold of 12.1 nmol/L which is ∼350 ng/dL based on our own clinical experience which was confirmed by Bhasin et al. [12]. Individuals who had androgen-dependent carcinoma of the prostate were excluded. Ethical guidelines formulated by the German Ärztekammer (German Medical Association) for observational studies in patients receiving standard treatment were followed. After receiving an explanation about the nature and the purpose of the study, all patients consented to be included in the registry and have their data analyzed. Participants were followed up routinely for updates in serum T and PSA levels, and several other physical, laboratory, and imaging test results.

Treatment assignment

Patients with PSA less than 4 ng/mL were given option of TRT. Receiving TRT or not was based on patient’s own choice at the beginning of study. Patients who decided to take TRT were classified as TRT group, and the rest were classified as non-TRT group. As described previously [13,14], patients on TRT received injections of 1000 mg of testosterone undecanoate with the second injection 6 weeks after the first injection, followed by 12-week intervals throughout the observation time. Since every injection was administered and documented in the urology office, the adherence to testosterone was 100%.

Scheduled follow-up and outcome assessment

Patients in the TRT group were seen and followed up four times a year which are the times when they returned for their next injection. Each time throughout the observation time, PSA and T levels were measured. Digital rectal examination and transrectal ultrasound were performed each time during the first year of treatment, thereafter at least two times a year. In the non-TRT group, PCa screening was performed routinely once or twice each year as part of a general health assessment. PCa diagnosis was confirmed through biopsy. If PSA increased to 4 ng/mL and above or increased by more than 0.75 ng/mL within 12 months, or if there were suspicious findings on digital rectal examination or trans-rectal ultrasound, a biopsy was performed to determine if PCa was present. The diagnosis procedures followed the European Association of Urology guidelines on PCa [15].

Measurements for dynamic patterns of T

Age at study entry

Males with abnormal function (below average) of reproductive organs such as erectile dysfunction would seek consultation from a doctor and obtained information on their T levels. If their T levels were below 12.1 nmol/L, they would be enrolled in the study after signing the informed consent sheet. Thus, we considered the age at study entry as an important indicator of the earliest time T levels dropped below 12.1 nmol/L, though the actual time of T levels dropped below 12.1 nmol/L might have occurred before age at study entry.

Maximum decline of T relative to baseline (MDRB)

The expression of this indicator used to measure the instability of serum T levels and calculate the maximum drop of T during follow-up period as compared to baseline level is as below: $$x_0-\underset{t}{\min }{x}_t$$

Where $x_0$ is the T level at study entry and $x_t$ is the T level at t (months) of follow-up.

Covariates

Information on baseline PSA level, family history of PCa, alcohol use, and smoking status was collected at entry into the study. Body mass index (BMI) was calculated based on height and weight measured at baseline. All covariates were selected a priori based on previous research and current knowledge about the relationship of those factors with TRT and risk of PCa.

Statistical analysis

Baseline characteristics and PCa occurrences during follow-up period were presented by group (treatment/control) using measures of central tendency and dispersion for continuous variables, and frequencies/percentages for categorical variables.

To evaluate the association between dynamic patterns of T and lifetime risk of PCa, we conducted Cox proportional hazards regression analyses between MDRB and risk of PCa during the follow-up period, after adjusting for baseline PSA level, age at entry, family history of PCa, BMI, alcohol use, and smoking status.

To explore the differences in dynamic patterns of T between treatment and control groups and examine whether the treatment group has more stable T levels over time, we compared the fluctuations of T levels during the follow-up period and the distributions of indicator (MDRB) between the two groups.

To investigate whether TRT can reduce the risk of PCa due to T declines at an early age, we conducted Cox proportional hazards regression analyses between age at study entry and risk of PCa in the treatment group and the control group respectively, after adjusting for baseline PSA level, family history of PCa, BMI, alcohol use, and smoking status. We conducted diagnostic tests and confirmed no violation of proportional hazards assumption in our models. We also calculated the difference of the coefficients assessing the relationship between age at study entry and PCa in the two groups and performed a Wald test to determine if it is significantly different from zero.

Sensitivity analysis

Given the controversial role of Klinefelter’s syndrome in the association between testosterone level and risk of PCa [16–18], we also conducted a sensitivity analysis after excluding 42 patients who had been diagnosed of Klinefelter’s syndrome when they were enrolled in the study.

All analyses were performed with R version 3.3.3. Tests results were considered statistically significant at α = 0.05. Risk of PCa was presented in a hazard ratio (HR) and its 95% confidence interval (CI).

Results

A total of 776 hypogonadal men aged 33–74 years were enrolled in this study, among which 400 men were on TRT and 376 were not. The average follow-up time is 7.03 years for the control group and 6.90 years for the treatment group. By the end of the study, 26 PCa cases were reported in the control group, as compared to 9 in the treatment group.

As shown in Table 1, the age distribution, PSA, BMI, and alcohol consumption are statistically significantly different between the two groups. Compared to participants in the control group, those in the treatment group were likely to be younger when entering the study (mean age at entry: 57.70 vs 63.94; years), less likely to drink alcohol (33.75% vs 49.37%), and had lower PSA (mean: 1.76 vs 2.43; ng/mL) and higher BMI (mean: 33.12 vs 30.12; kg/m²).

Table 1. Characteristics of participants, by group.

	Control (n = 376)		Treatment (n = 400)
Characteristics	Mean ± SE^a	Range	Mean ± SE^a	Range	p-value
	N (%)		N (%)
Baseline
Age at study entry (Years)	63.94 ± 4.68	45–74	57.70 ± 7.40	33–71	<.001
Follow-up (Years)	7.03 ± 1.83	2–11	6.90 ± 2.86	0.75–10.25	.476
T (nmol/L)	9.70 ± 1.15	5.89–12.13	9.82 ± 1.24	5.89–12.13	.1465
PSA (ng/mL)	2.43 ± 1.27	0.20–7.90	1.76 ± 0.93	0.08–3.90	<.001
BMI (kg/m^2)	30.12 ± 4.22	22.15–46.98	33.12 ± 5.42	21.91–46.51	<.001
Family history (Yes)	45 (11.97)	–	39 (9.75)	–	.3556
Smoking (Yes)	138 (36.70)	–	154 (38.50)	–	.6565
Alcohol (Yes)	186 (49.47)	–	135 (33.75)	–	<.001
Endpoint
PCa (Yes)	26 (6.91)	–	9 (2.25)	–	.0017

^a Mean ± SE for numerical variables and N (%) for categorical variables.

As presented in Table 2, the maximum drop of T level during the follow-up period, which is calculated in MDRB, is significantly lower in the treatment group as compared to that in the control group. Specifically, the maximum MDRB in the control group is 6.587 nmol/L, whereas in the treatment group, the corresponding value is only 2.774 nmol/L. If we use 75th percentile of MDRB (2.08 nmol/L) in the control group as the cutoff point, there are 118 (31.38%) participants in the control group with an MDRB equal to or larger than 2.08 nmol/L, as compared to only 1 (0.25%) in the treatment group. The mean of MDRB is significantly different between the two groups (1.553 nmol/L VS 0.013 nmol/L; p value < .001). Overall, the hazard ratio (HR) associated with higher MDRB (≥2.08 nmol/L) is 2.48 (95%CI: 1.20–5.13), after controlling for PSA, age at study entry, family history of PCa, BMI, alcohol consumption, and smoking status (Table 3). If we treat MDRB as a continuous variable, the HR associated with one unit increase of MDRB is 1.43 (95%CI: 1.11–1.84) (data not shown).

Table 2. Distribution of MDRB (nmol/L) describing the dynamic pattern of T, by group.

	Control			Treatment
Indicator	N (%)	Range	Mean ± SE	N (%)	Range	Mean ± SE	p-value
MDRB (continuous)	376 (100.00)	0–6.587	1.553 ± 1.093	400 (100.00)	0–2.774	0.013 ± 0.184	<.001
MDRB (categorical)
<2.08	258 (68.62)	–	–	399 (99.75)	–	–	<.001
≥2.08	118 (31.38)	–	–	1 (0.25)	–	–

Table 3. Cox proportional hazards regression of PCa on MDRB (nmol/L), PSA, age at study entry, BMI, family history of PCa, alcohol use, and smoking status.

Covariates	HR	95%CI	p-value
MDRB (≥2.08^a)	2.48	1.20–5.13	.014
PSA	1.59	1.29–1.96	<.001
Age at study entry	1.05	0.97–1.15	.212
BMI	1.05	0.97–1.13	.208
Family history	27.35	11.34–65.95	<.001
Alcohol	1.47	0.59–3.65	.410
Smoking	0.94	0.38–2.33	.887

^a 2.08 nmol/L is the 75th percentile of MDRB in the control group.

Table 4 presents the differences in the effect of age at study entry (a surrogate for the first time T dropping below 12.1 nmol/L) on risk of PCa between treatment and control groups. In the control group, the adjusted HR associated with a one-year increase of age at study entry is 0.64 (95%CI: 0.53–0.78), indicating a higher lifetime risk of PCa for males with T dropping below 12.1 nmol/L at their earlier age of life. In the treatment group, the corresponding adjusted HR for an additional year increase of age at study entry is 1.09 (95%CI: 0.86–1.39, p = .471), which is not statistically significant, suggesting “elimination” or “alleviation” of the adverse effect of T dropping at earlier time of life. The difference in the effects (coefficients) of age at study entry on PCa between the two groups is significantly different from 0 (p = .00087), hence we conclude TRT significantly reduces the risk of PCa for males with T drop earlier in their lives.

Table 4. Hazard ratios associated with one-year increase in age at study entry, adjusting for family history of PCa, PSA, BMI, alcohol use, and smoking status, by group.

Group	HR	95%CI	p-value
Treatment	1.09	0.86–1.39	.471
Control	0.64	0.53–0.78	<.001

Figure 1 shows that the baseline T levels were about the same in the two groups. During years of follow-up, the treatment group had higher than baseline T levels and on average higher T levels compared to those in the control group.

Figure 1. T levels during follow-up period, by group.

Excluding patients who had been diagnosed with Klinefelter’s syndrome in the analysis did not affect the observed association (results not shown).

Discussion

The findings from this registry study with 776 hypogonadal patients revealed that risk of PCa is significantly associated with unstable serum T levels among hypogonadal males, and males treated with TRT tend to have more stable T levels as compared to those who did not. By receiving TRT, the PCa risk associated with T deficiency at a young age can be reduced.

Accumulating evidence has demonstrated an important association between low T levels and PCa risk [7,19–21], and TRT has been considered an effective treatment for men with symptomatic T deficiency [7]. The last decade has seen a rise in TRT worldwide [22], though controversies exist regarding the clinical use of TRT in patients who have a personal history of PCa or are at high risk for PCa. Recent evidence shows androgen/testosterone therapy may reduce PCa risk. In a randomized, double-blinded, placebo-controlled trial of 44 men aged 44–78 years with serum T lower than 10.4 nmol/L, Marks and colleagues found the PCa incidence was 9.5% in the T treatment group which were assigned to receive 150 mg of testosterone enanthate every 2 weeks for 6 months, as compared to 21% in the placebo group [23]. A recent study reviewing 11 placebo-controlled trials revealed a higher incidence of PCa detected in the placebo group, which indicates a protective role of T treatment in preventing PCa [24]. Other studies show TRT in patients treated with radiation therapy improved hypogonadal symptoms without resulting in higher PCa recurrence or worse clinical outcomes [25,26]. T treatment was not associated with increased risk of any PCa [27], and long-term use of TRT did not increase risk of high-grade PCa [28]. Though more rigorous studies are needed to determine the safety of T treatment, newer data suggest TRT might be a viable option for men with T deficiency to ameliorate hypogonadal symptoms, as well as prevent PCa.

Since the advent of TRT, supplementation has been used to treat the secondary effects of hypogonadism, including decreased libido, impairment in cognition, reduced muscle mass, and metabolic abnormalities [29–32]. It significantly improves serum total T, which is closely related to prostate health and an essential metabolic hormone for maintaining overall physiological function among males [13]. However, whether TRT affects prostate health and metabolism via other mechanisms beyond merely elevating serum T levels from “low” concentration category at the beginning to “high” concentration category in the end has not yet been determined. Since the intra- and inter-individual biological variation in T can be large [33], assessing the effect of TRT based on two measurements taken at the starting and ending points of the study may be inadequate [34]. Our recent study investigating the longitudinal dynamic patterns of T on PCa development among 376 men with untreated hypogonadism for 7–11 years found hypogonadal males with unstable T levels after hypogonadism diagnosis or with notable T level declines at a younger age have a higher risk of PCa [5]. In the current study, we derived an index to describe the longitudinal variations of T over the study period for each study participant and found larger variations of serum T levels were significantly associated with increased risk of PCa, and the treatment group was more likely to have stable serum T levels. These findings indicate TRT may reduce PCa via stabilizing serum T levels in addition to increasing serum T levels, but it warrants further investigation.

In this study, we also found TRT could reduce the PCa risk associated with abnormal T decline at young ages. In males, T levels increase during puberty and adolescence, reaching a peak in young to middle adulthood and then gradually decrease when males enter their late adulthood. There is a natural decline of T levels with advancing age, typically 1–3% per year [35–37]. Compared to a natural and slow decrease in T levels during males’ late adulthood, a very low T level observed at an earlier age may indicate abnormally rapid declines during certain periods of life previously, which is associated with increased risk of PCa [5]. As TRT may reduce this risk by normalizing and stabilizing an individual’s T levels, surveillance on the dynamic changes of T levels over time among males starting at young adulthood, especially those at high risk for PCa (e.g. men with family history of PCa, African Americans), may be essential to ensure timely initiation of T therapy and prevent patients from worrisome symptoms and cancer.

To our knowledge, this is the first study to examine whether TRT reduces PCa risk via stabilizing serum T levels beyond merely elevating an individual’s serum T levels, which provides insights into the development of future surveillance strategy to monitor if maintaining stable T levels may be an additional factor needing to be considered. With up to 11 years biannual repeated measurement of T, we were able to assess the effect of TRT on longitudinal variations of serum T and its influence on PCa. Limitations of this study should be noted. Firstly, the study subjects were limited to a European population and those with hypogonadism, which may weaken the external validity of this study. At this time, our observations can only be applied to European males with testosterone levels ≤12.1 nmol/L (∼350 ng/dL). Future studies concerning the study population with different characteristics and with no specific inclusion criterion are needed to further verify our study findings. Secondly, a patient’s decision to receive T treatment is likely not at random, this may involve confounders we were not able to control for in the analyses, resulting in biased results. Thirdly, the index we derived to measure the maximum drop of T during follow-up period as compared to baseline level has not been used in other longitudinal data. Future studies are needed to verify our study findings.

In conclusion, unstable serum T levels are significantly associated with an increased risk of PCa in hypogonadal males. TRT may reduce this risk by elevating the testosterone level and maintaining it within the normal range. Rigorous surveillance on the dynamic changes of T levels over time among males starting at young adulthood, especially those at high risk for PCa, may be essential to ensure timely treatment and prevent patients from worrisome symptoms and cancer.

Disclosure statement

Dr. Farid Saad has a financial relationship with Bayer AG.

Additional information

Funding

This study is not funded.