Can Testosterone Treatment in Elderly Men with Hypogonadism Improve Metabolic Syndrome and Health-Related Quality of Life?

Introduction: Late-onset hypogonadism (LOH) which is aging-associated Hypogonadism, is diagnosed when declining testosterone concentrations in the aging male cause unwanted symptoms, metabolic or sexual deterioration, like increased visceral obesity with related metabolic syndrome (MetS) parameters or components, insulin resistance, erectile dysfunction (ED), reduced bone density and muscle strength. Restoring testosterone to physiological concentrations has beneficial effects on many of these symptoms; however, it is not known whether these effects can be sustained in the long term.

Aims: The target was to investigate testosterone treatment with testosterone undecanoate (TU) 1000mg has a long-term and sustained effect on parameters affected by the MetS in men with Late-onset hypogonadism (LOH) and erectile dysfunction (ED), to evaluate if long-term testosterone treatment can improve the overall health-related quality of life in, and to establish the safety of long-term testosterone treatment.

Methods: 261 patients (mean age 59.5 ± 8.4 years) diagnosed with LOH and ED were treated with long-acting TU in a prospective, observational, and longitudinal registry study. Men received intramuscular injections of 1,000 mg TU at day 1, at week 6, and every 3 months thereafter.

Main Outcome Measures: Parameters affected by the MetS, including obesity parameters (body weight, waist circumference, and body mass index [BMI]), total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, glucose, HbA1c (glycated hemoglobin), and blood pressure, as well as total testosterone levels. Health-related quality of life, were assessed.

Results: We found TU significantly improved obesity parameters (body weight, waist circumference, and BMI) and lowered total cholesterol, LDL cholesterol, triglycerides, fasting blood glucose, HbA1c, and blood pressure over the 5-year study. HDL cholesterol was increased. TU treatment resulted in a sustained improvement in erectile function and muscle and joint pain, which contributed to an improvement in long-term health-related quality of life. Furthermore, we found a relationship between health-related quality of life and waist circumference. Finally, we found no evidence that long‐term treatment with TU increases the risk of prostate carcinoma.

Conclusion: Long‐term TU in men with LOH and ED reduces obesity parameters and improves metabolic syndrome and health‐related quality of life.

Late‐onset hypogonadism (LOH) is diagnosed when declining testosterone concentrations in the aging male cause unwanted symptoms such as erectile dysfunction (ED), lack of physical strength, depressed mood, and visceral obesity [1-6]. It is thought that over 40% of men between the ages of 60 and 69 years will develop some form of ED [7]. Recent studies have demonstrated a close relationship between testosterone and ED [8,9] and show testosterone to be an efficient treatment for ED and other symptoms of LOH. Total and free testosterone concentrations are reported to be inversely related to abdominal obesity [10-12]. The hypogonadal‐obesity cycle described by Cohen [13] and Kapoor and colleagues [14] suggests that in the hypogonadal state, there is an increase in the deposition of abdominal adipose tissue, further reducing testosterone and resulting in progressive hypogonadism. Weight loss in obese men has been shown to produce a significant rise in both total and free testosterone concentrations in proportion to the degree of weight loss [15]. Similarly, restoring testosterone levels in obese men reduces body mass index (BMI) and visceral fat mass [16,17]. Patients undergoing testosterone undecanoate (TU) treatment show an improvement in body composition that includes an increase in lean body mass and a decrease in fat tissue [18]. Conversely, patients receiving gonadotropin‐releasing hormone agonist therapy (which induces a state of hypogonadism) display an increase in fat mass and a concomitant reduction in lean mass [19]. Obesity and low testosterone are also associated with insulin insensitivity, with testosterone replacement therapy having beneficial effects on obesity and insulin resistance [20]. Similarly, a 3‐month course of testosterone replacement therapy in hypogonadal men with type 2 diabetes mellitus was reported to improve insulin sensitivity [20]. Men diagnosed with LOH often suffer from the metabolic syndrome (MetS), which is generally found in viscerally obese patients with insulin resistance. In fact, insulin resistance plays a key role in the pathogenesis of the MetS. The prevalence of the MetS is significantly higher in men with LOH than in healthy controls [21]. According to the International Diabetes Federation [22], MetS is defined by the combination of central obesity and any two or more of the following factors: hypertriglyceridemia, low high‐density lipoprotein (HDL) cholesterol, hypertension, and raised fasting blood glucose or previously diagnosed type 2 diabetes mellitus. Evidence that restoring testosterone levels improves parameters affected by the MetS comes from clinical studies demonstrating reductions in waist circumference, fat mass, low‐density lipoprotein (LDL) cholesterol, total cholesterol, triglycerides, and blood pressure, as well as raised HDL cholesterol, following testosterone treatment in hypogonadal patients [23,24].

Men undergoing androgen deprivation therapy experience a suppression of sexual desire, with significant reductions in frequency, magnitude, duration, and rigidity of nocturnal erections [25,26]. Conversely, penetration, maintenance of erection, and desire all improve with testosterone treatment, as observed from IIEF (International Index of Erectile Function) scores [8,9,27,28]. Such studies clearly demonstrate that testosterone concentrations are closely associated with erectile function, sexual interest, and sexual activity. Furthermore, hypogonadal men undergoing testosterone therapy show improved parameters of well‐being, bone density, muscle mass, physical strength, sexual function, and libido [29]. These data provide evidence that testosterone concentrations have a significant effect on health‐related quality of life in men, an effect that has been the subject of only a handful of investigations.

There is currently no evidence that testosterone treatment increases the risk of prostate disease using modern guidelines [30]. Furthermore, testosterone treatment can improve LUTS (IPSS score) in all categories (mild, moderate and severe) also independent of prostate size [31, 32, 33].

The aims of the present study were (i) to investigate whether treatment with TU has a long‐term and sustained effect on parameters affected by the MetS in men with LOH and ED; (ii) to determine whether long‐term testosterone treatment can improve the overall health‐related quality of life in these men; and (iii) to establish the safety of long‐term testosterone treatment.

Study Design

From November 2004, 261 patients (mean age 59.5 ± 8.4 years) diagnosed with LOH and ED were treated with long‐acting TU (Nebido®, Bayer Pharma, Berlin, Germany) in a prospective, observational, and longitudinal registry study. All patients with ED were diagnosed with LOH, thus excluding other forms of hypogonadism. In addition, 2% of patients in the cohort had Klinefelter syndrome. All patients gave their written informed consent to be included in the study, which was conducted according to ethical guidelines for observational studies as formulated by the Bundesärztekammer (the German Medical Association) and followed the principles outlined in the Helsinki Declaration of 1975, as revised in 1983. Men with a total testosterone concentration of ≤3.5 ng/mL (12 nmol/L) and documented symptoms of ED (IIEF‐5 score ≤21) met the inclusion criteria. Men received intramuscular injections of 1,000 mg TU at day 1, week 6, and every 3 months thereafter. The mean duration of treatment was 4.25 years, with a maximum duration of 7 years. A total of 31 patients took phosphodiesterase type 5 (PDE5) inhibitors during follow‐up. Demographic data were collected at baseline, a summary of which is shown in Table 1.

Assessment of Outcome

To assess the effect of long‐term TU treatment, all parameters affected by the MetS, including obesity parameters (body weight, waist circumference, and BMI), total cholesterol, LDL/HDL, triglycerides, glucose, HbA1c (glycated hemoglobin), and blood pressure, in addition to total testosterone levels, were measured at baseline and at every subsequent visit. Total testosterone concentrations among the study population were plotted against time. Linear regression analysis was used to assess the changes in HDL, LDL, triglycerides, blood pressure, and serum glucose in the entire cohort over time. Quality of life was measured using the International Prostate Symptom Score (IPSS), the Aging Male Symptoms (AMS) scale, and the IIEF-5. The percentage of patients reporting joint and muscle pain was calculated at each visit and recorded in a binary fashion.

Table 1: Demographic characteristics of the patient cohort collected at baseline.

Statistical Analysis

Statistical analyses were performed with the statistics program SPSS® (version 18, IBM, Armonk, NY, USA). Analysis of variance (ANOVA) was used to compare categorical and continuous variables. Comparisons between categorical variables were performed using χ2‐test. Spearman's rank correlation coefficients were used to evaluate possible relationships between continuous variables. Results are expressed as means ± SD unless otherwise stated. A P value of lessthan 0.05 was considered significant. The declining patient numbers over the course of the study do not reflect dropouts but result from the registry design, as described previously [17].

Metabolic Syndrome

Long‐term TU treatment improved all parameters affected by the metabolic syndrome in patients with LOH. The prevalence of the metabolic syndrome among the patient cohort fell from 56percentage at baseline to 30percentage after 5.5 years of testosterone treatment.

Total Testosterone

The mean testosterone concentration before treatment commenced was 2.23 ± 0.6 ng/mL (7.72 ± 2.07 nmol/L), which increased within 2 years to 5.25 ± 0.99 ng/mL (18.19 ± 3.44 nmol/L), remaining stable thereafter.

Obesity Parameters

Body weight, waist circumference, and BMI were measured at baseline and quarterly after treatment with TU. Body weight decreased from 100.1 ± 14.0 kg to 92.5 ± 11.2 kg, and waist circumference was reduced from 107.7 ± 10.0 cm to 99.0 ± 9.1 cm. BMI declined from 31.7 ± 4.4 kg/m2 to 29.4 ± 3.4 kg/m2 (P lessthan 0.0001).

Lipids

Total cholesterol was reduced in the patient cohort from 256.24 ± 51.06 mg/dL at baseline to 212.2 ± 40.88 mg/dL at the end of the 5‐year study period (Figure 1 A). LDL cholesterol was reduced from 157.09 ± 28.43 mg/dL to 126.41 ± 33.7 mg/dL (Figure 1B). Triglycerides reduced significantly from 252.05 ± 95.23 mg/dL to 199.04 ± 52.34 mg/dL (P lessthan 0.0001; β = −0.77; Figure 1C), and HDL cholesterol increased significantly from 41.34 ± 12.15 mg/dL to 55.62 ± 14.66 mg/dL (P lessthan 0.05; β = 0.53; Figure 1D). Furthermore, the ratio of total cholesterol to HDL cholesterol was reduced from 6.84 ± 2.84 to 4.09 ± 1.19 over the course of the 5-year study.

Figure 1: Long‐term TU treatment improves the lipid profile. Total cholesterol (A), LDL cholesterol (B), triglyceride (C), and HDL cholesterol (D) concentrations (mg/dL) are shown for baseline and each year over the 5‐year study. *P lessthan 0.0001 vs. baseline. P values above bars represent significance vs. previous year. Error bars represent standard deviation. ns = not significant.

Glucose

Over the course of the study, reductions were observed in fasting blood glucose (111.92 ± 36.69 mg/dL to 99.02 ± 18.1 mg/dL; P lessthan 0.0001; β = −0.67; Figure 2) and in HbA1c (from 6.55 ± 1.2percentage to 5.63 ± 0.64percentage; Figure 3).

Figure 2: Fasting glucose concentration (mg/dL) was measured at baseline and yearly over the five-year study. *P lessthan 0.0001 vs. baseline. P values above bars represent significance vs. previous year. Error bars represent standard deviation. ns=not significant.

Figure 3: HbA1c levels (percentage) measured for baseline and each year over the 5‐year study. *P lessthan 0.0001 vs. baseline. P values above bars represent significance vs. previous year. Error bars represent standard deviation. ns = not significant.

Blood Pressure

Systolic blood pressure was significantly reduced from 137.39 ± 13.05 mm Hg to 122.35 ± 5.96 mm Hg (P lessthan 0.0001; Figure 4 A) and diastolic blood pressure from 82.11 ± 9 mm Hg to 77.68 ± 4.07 mm Hg (P lessthan 0.0001) over the 5-year study period (Figure 4B).

Figure 4: Long‐term TU treatment reduces blood pressure. Measurements of systolic blood pressure (A) and diastolic blood pressure (B) (mm Hg) are shown for baseline and each year over the 5‐year study. *P lessthan 0.0001 vs. baseline. P values above bars represent significance vs. previous year. Error bars represent standard deviation. ns = not significant.

Health‐Related Quality of Life

Quality of life was measured in men undergoing testosterone replacement therapy using the IPSS, the AMS scale, and the truncated form of the IIEF (questions 1–5 plus 15, maximum score 30) as indicators of erectile function. Complaints of joint and muscle pain were also recorded. Over the 5.5‐year treatment period, the mean IPSS score fell from 10.35 at baseline to 6.31 (Figure 5 A). The AMS score was reduced from 54.27 ± 8.34 to 31.18 ± 5.5 (Figure 5B), and the IIEF‐5 score increased significantly from 7.8 ± 3.32 at baseline to 20.1 ± 6.3 (P lessthan 0.0001; Figure 5C). The percentage of patients complaining of joint and muscle pain decreased from 58percentage at baseline to just 1percentage after 5.5 years of testosterone treatment (Figure 5D). No cardiovascular events were reported during the treatment period.

Figure 5: TU treatment improves health‐related quality of life. Quality of life was measured using the IPSS (A), the AMS (B), and the IIEF‐5 (C). The percentage of men in the cohort complaining of joint and muscle pain (D) was also recorded over the 5‐year period.

Predictors of Health‐Related Quality of Life

Observational regression analysis revealed a negative correlation between health‐related quality of life as scored by the IIEF‐5 and waist circumference (P lessthan 0.000). A positive correlation was observed between health‐related quality of life as scored by both the AMS (P lessthan 0.012) and the IPSS (P lessthan 0.001) and waist circumference. Furthermore, a negative correlation was found to exist between the IIEF‐5 score (P lessthan 0.000) and weight, which also positively correlated with the IPSS score (P lessthan 0.000). BMI was not associated with any indicators of health‐related quality of life. Among weight, BMI, and waist circumference, the latter was the best predictor of health‐related quality of life in men with LOH manifesting as sexual symptoms, voiding symptoms, and other psychosomatic symptoms.

Prostate Cancer Risk

A total of 2.3percentage of patients undergoing TU treatment developed prostate cancer, an incidence of 54.4 per 10,000 patient‐years, providing evidence that prostate cancer risk is not increased by long‐term testosterone treatment.

The present study demonstrates that long‐term treatment with TU in men with LOH and ED reduces the three obesity parameters body weight, waist circumference, and BMI and that this reduction can be sustained over a 5‐year period. These results confirm previous findings [16,17], and the weight loss observed in this study was greater than that observed with lifestyle changes, with or without the use of pharmacological intervention, in all previous similar studies [16,17,34]. The weight loss observed in hypogonadal men treated with TU suggests that testosterone may be a physiological modulator of body composition due to its role in regulating carbohydrate and fat metabolism, as well as promoting myogenesis while inhibiting adipogenesis [24,35-37]. Indeed, androgen deficiency has been shown in a recent study to result in a loss of lean mass and muscle size and strength [38]. Thus, these findings may be explained, in part, by a reduction in fat mass attributable to changes in metabolism modulated by testosterone. In addition, testosterone increases motivation, enhances mood, and promotes a more active lifestyle, resulting in increased physical activity and subsequent energy expenditure, thus contributing to further weight loss [16,17]. Furthermore, a recent meta‐analysis concluded that weight loss contributes to an improvement in testosterone levels, demonstrating a positive feedback loop [39].

The present study demonstrates that long‐term treatment with TU improves the individual parameters affected by the MetS, including lipids, glucose, and blood pressure, and shows that testosterone treatment results in a sustained improvement in other symptoms associated with LOH as outlined by the European Association of Urology and the recent International Society for Sexual Medicine Standards Committee guidelines on male hypogonadism, such as erectile function and muscle and joint pain, contributing to an improved overall long‐term health‐related quality of life [40,41]. These data confirm previous studies in which testosterone was shown to significantly improve symptoms of the MetS in addition to improving sexual function and vitality, lower urinary tract symptoms, and the overall quality of life in men with testosterone deficiency [42-48]. Such studies provide evidence that testosterone ameliorates the risk of cardiometabolic diseases and improves the quality of life in hypogonadal men [49-51] and may explain the increase in physical activity associated with testosterone treatment [52]. Indeed, testosterone replacement therapy has previously been demonstrated to reduce the risk of cardiovascular mortality by improving metabolic parameters, although further studies are required to fully determine the safety of TRT in men with cardiovascular disease [51,53,55]. The relationship between testosterone and ED is complex. Evidence from both human and animal studies demonstrates only a weak relationship between low testosterone and ED [56,57]. Additionally, as testosterone modulates both the initiation and the end of the erectile process through nitric oxide (NO) synthase and PDE5 stimulation respectively, it has only a modest net effect on erection. Hence, erections are still possible in hypogonadal conditions, where decreased formation of cyclic guanosine monophosphate (cGMP) due to impaired NO production is counterbalanced by reduced PDE5 activity and cGMP hydrolysis. The main physiological action of testosterone is therefore to regulate the timing of the erectile process as a function of sexual desire, coordinating erections with sex [58,59]. A trophic effect of testosterone on penile architecture has also been demonstrated in different animal species [56,60]. Thus, treating hypogonadism restores impaired penile erections in experimental animal models, as well as in the clinical setting, whereas testosterone administration to otherwise eugonadal individuals has little effect.

It must be considered that the testosterone levels observed with TU injections were trough levels, as blood samples were taken 3 months after each injection, just prior to the next one. Evidence from pharmacokinetic studies shows that testosterone levels peak in the second week after TU injection [61,62], and thus any dose‐dependent effects observed may reflect this. As long‐term treatment with TU is required to achieve optimal effects, the length of this study, which allowed time for the optimal effects of TU to be observed, provides a useful timescale from which hypogonadal patients will benefit. For instance, quality of life and lipid profile are known to improve within around 4 weeks, although maximal results can take up to 12 months [63]. Evidence from a recent study demonstrates that estradiol plays an important role in the regulation of body fat and sexual function; thus, a deficiency in this hormone may underlie a number of consequences of male hypogonadism [38]. It is therefore important to recognize that estradiol deficiency may have been a factor in the present study, and as testosterone levels improved, estradiol levels likely increased in parallel. Finally, we found no evidence that long‐term treatment with TU increased the risk of prostate carcinoma. In the present study, a total of 2.3% of patients undergoing TU treatment developed prostate cancer, an incidence of 54.4 per 10,000 patient‐years. A previous cancer screening trial reported that 2,820 men out of a total of 38,343 were diagnosed with prostate cancer, representing an incidence of 116 per 10,000 patient‐years (7.35%) [64]. In the European Randomized Study of Screening for Prostate Cancer, involving 82,816 patients, 8.2% of patients were diagnosed with prostate cancer, an incidence of 96.6 per 10,000 person years [65]. On the basis of the results from these extensive screening trials, the incidence of prostate cancer in our cohort was lower than expected [66]. One of the limitations of the present study is the nature of the registry design. This single-center, open-label study is not a randomized controlled study, therefore limiting the scope of interpretation of the presented findings. However, our findings were recently confirmed in a small but controlled study [66].

We found that TU improved obesity parameters; lowered total cholesterol, LDL cholesterol, triglycerides, fasting blood glucose, HbA1c, and blood pressure; and increased HDL cholesterol over the 5‐year study. Testosterone treatment improved erectile function and muscle and joint pain, which contributed to an improvement in long‐term health‐related quality of life. Furthermore, we found waist circumference to be the best predictor of health‐related quality of life. Finally, we found no evidence that long‐term treatment with TU increases the risk of prostate carcinoma.