1567
ORIGINAL RESEARCH—ENDOCRINOLOGY Long-Term Testosterone Treatment in Elderly Men with Hypogonadism and Erectile Dysfunction Reduces Obesity Parameters and Improves Metabolic Syndrome and Health-Related Quality of Life Dany-Jan Yassin, MBBS,* Gheorghe Doros, PhD,† Peter G. Hammerer, MD, PhD,* and Aksam A. Yassin, MD, PhD, EdD‡§ *Department of Urology and Onco-Urology, Klinikum Braunschweig, Braunschweig, Germany; †Department of Epidemiology and Statistics, Boston University School of Public Health, Boston, MA, USA; ‡Institute of Urology and Andrology, Norderstedt-Hamburg, Germany; §Dresden International University, Dresden, Germany DOI: 10.1111/jsm.12523
ABSTRACT
Introduction. Late-onset hypogonadism (LOH) is diagnosed when declining testosterone concentrations in the aging male cause unwanted symptoms such as erectile dysfunction (ED), reduced bone density and muscle strength, and increased visceral obesity. Testosterone deficiency is also associated with insulin resistance and the metabolic syndrome (MetS). 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. To investigate whether treatment with testosterone undecanoate (TU) has a long-term and sustained effect on parameters affected by the MetS in men with LOH and ED, to determine whether long-term testosterone treatment can improve the overall health-related quality of life in these men, and to establish the safety of long-term testosterone treatment. Methods. Two hundred sixty-one 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 and 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. Yassin DJ, Doros G, Hammerer PG, and Yassin AA. Long-term testosterone treatment in elderly men with hypogonadism and erectile dysfunction reduces obesity parameters and improves metabolic syndrome and health-related quality of life. J Sex Med 2014;11:1567–1576. Key Words. Late-Onset Hypogonadism; Erectile Dysfunction; Metabolic Syndrome; Obesity; Testosterone; Testosterone Replacement Therapy; Cholesterol; Glucose; Blood Pressure; Body Mass Index; Prostate Cancer; Lower Urinary Tract Symptoms
© 2014 International Society for Sexual Medicine
J Sex Med 2014;11:1567–1576
1568 Introduction
L
ate-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 highdensity lipoprotein (HDL) cholesterol, hypertension, and raised fasting blood glucose or previously
J Sex Med 2014;11:1567–1576
Yassin et al. 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]. 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 longterm testosterone treatment. Methods
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
Testosterone Improves Health-Related Quality of Life Table 1 Demographic characteristics of the patient cohort collected at baseline Parameter
n
Proportion (%)
2
BMI (kg/m ) Normal weight (BMI ≤ 24.9) Overweight (BMI 25–29.9) Obese (BMI 30+) Waist circumference (cm) Normal (102) Known comorbidities at baseline Hypertension Type 2 diabetes Dyslipidemia Coronary artery disease Erectile dysfunction Benign prostatic hyperplasia/lower urinary tract symptoms Prostatitis Osteoporosis
11 88 162
4 34 62
8 74 179
3 28 69
117 80 87 32 261 150
45 31 33 12 100 57
30 14
11 5
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
1569
pain was calculated at each visit and recorded in a binary fashion.
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
ORIGINAL RESEARCH—ENDOCRINOLOGY Long-Term Testosterone Treatment in Elderly Men with Hypogonadism and Erectile Dysfunction Reduces Obesity Parameters and Improves Metabolic Syndrome and Health-Related Quality of Life Dany-Jan Yassin, MBBS,* Gheorghe Doros, PhD,† Peter G. Hammerer, MD, PhD,* and Aksam A. Yassin, MD, PhD, EdD‡§ *Department of Urology and Onco-Urology, Klinikum Braunschweig, Braunschweig, Germany; †Department of Epidemiology and Statistics, Boston University School of Public Health, Boston, MA, USA; ‡Institute of Urology and Andrology, Norderstedt-Hamburg, Germany; §Dresden International University, Dresden, Germany DOI: 10.1111/jsm.12523
ABSTRACT
Introduction. Late-onset hypogonadism (LOH) is diagnosed when declining testosterone concentrations in the aging male cause unwanted symptoms such as erectile dysfunction (ED), reduced bone density and muscle strength, and increased visceral obesity. Testosterone deficiency is also associated with insulin resistance and the metabolic syndrome (MetS). 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. To investigate whether treatment with testosterone undecanoate (TU) has a long-term and sustained effect on parameters affected by the MetS in men with LOH and ED, to determine whether long-term testosterone treatment can improve the overall health-related quality of life in these men, and to establish the safety of long-term testosterone treatment. Methods. Two hundred sixty-one 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 and 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. Yassin DJ, Doros G, Hammerer PG, and Yassin AA. Long-term testosterone treatment in elderly men with hypogonadism and erectile dysfunction reduces obesity parameters and improves metabolic syndrome and health-related quality of life. J Sex Med 2014;11:1567–1576. Key Words. Late-Onset Hypogonadism; Erectile Dysfunction; Metabolic Syndrome; Obesity; Testosterone; Testosterone Replacement Therapy; Cholesterol; Glucose; Blood Pressure; Body Mass Index; Prostate Cancer; Lower Urinary Tract Symptoms
© 2014 International Society for Sexual Medicine
J Sex Med 2014;11:1567–1576
1568 Introduction
L
ate-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 highdensity lipoprotein (HDL) cholesterol, hypertension, and raised fasting blood glucose or previously
J Sex Med 2014;11:1567–1576
Yassin et al. 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]. 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 longterm testosterone treatment. Methods
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
Testosterone Improves Health-Related Quality of Life Table 1 Demographic characteristics of the patient cohort collected at baseline Parameter
n
Proportion (%)
2
BMI (kg/m ) Normal weight (BMI ≤ 24.9) Overweight (BMI 25–29.9) Obese (BMI 30+) Waist circumference (cm) Normal (102) Known comorbidities at baseline Hypertension Type 2 diabetes Dyslipidemia Coronary artery disease Erectile dysfunction Benign prostatic hyperplasia/lower urinary tract symptoms Prostatitis Osteoporosis
11 88 162
4 34 62
8 74 179
3 28 69
117 80 87 32 261 150
45 31 33 12 100 57
30 14
11 5
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
1569
pain was calculated at each visit and recorded in a binary fashion.
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
