- Email: [email protected]
Androgen Deprivation Therapy in Patients with Advanced Prostate Cancer and Type 2 Diabetes Impairs Glucose and Lipid Metabolism
WCMH Abstracts 61
63
TESTOSTERONE ADMINISTRATION DECREASES CAROTID ARTERY INTIMA MEDIA THICKNESS AS A MARKER OF IMPAIRED VASCULAR INTEGRITY IN MIDDLE-AGED OVERWEIGHT MEN
TESTOSTERONE AND OBESITY — A REVIEW OF THE CURRENT LITERATURE
Michael Zitzmann 1,∗ , Elena Vorona 1 , Melanie Wenk 1 , Farid Saad 2 , Eberhard Nieschlag 1
1
Center for Reproductive Medicine and Andrology, University Clinics of Muenster, Germany, 2 Bayer Schering Pharma AG, Scientific Affairs Men’s Healthcare, Berlin, Germany, and Gulf Medical University, Ajman, UAE E-mail address: [email protected] (M. Zitzmann).
1
Background: Overweight in younger people is an increasing problem, being a clinically significant risk factor for the development of cardiovascular disease in later life. Epidemiological studies suggest that testosterone (T) deficiency in men is associated with the amount of adipose tissue and can augment its adverse effects, possibly by propagating the shedding of pro-inflammatory substances. These approaches focus on the presence of cardiovascular events in older men. In younger men, carotid artery intima media thickness (IMT) as an indicator of intravascular inflammation represents an early marker of subclinical vessel damage. We speculated whether the administration of a depot-form of T (intramuscular T-undecanoate) might have beneficial effects on IMT in younger overweight men. Methods: 42 middle-aged, healthy men were included in a body mass index (BMI)matched, controlled interventional study, receiving 4 intramuscular injections of 1000 mg of T-undecanoate in increasing intervals in weeks 0, 6, 14, 24. Group 1 (n = 21, 33.3 ± 7.7 years) had a BMI > 25 kg/m2 . Group 2 (controls, n = 21, 31.2 ± 6.2 years) had a BMI < 25 kg/m2 . Primary endpoint parameter was IMT, secondary endpoints were lipoprotein and triglyceride concentrations. Safety parameters were PSA and hematocrit. A classical threshold for androgen deficiency was not defined as an inclusion criterium. Results: Baseline characteristics were markedly different in Group 1 vs Group 2. Mean IMT was 0.86 ± 0.1 mm vs 0.75 ± 0,1 mm, p = 0.001; total T concentrations were12.6 ± 4.2nmol/L vs 16.2 ± 3.4nmol/L, p = 0.004, respectively. End-of-treatment assessments revealed IMT to be significantly decreased in Group 1 (0.63 ± 0.1 mm) as well as in Group 2 (0.59 ± 0.1 mm), p < 0.001 by paired t-tests for both groups, respectively. ANCOVA assessments for repeated measurements revealed the overall treatment effect to be augmented by lower baseline T levels (p = 0.002) and higher baseline BMI (p = 0.02). Corresponding alterations were seen in body composition. No significant changes in these healthy men were noted for lipoprotein concentrations, blood pressure, PSA or hematocrit. Conclusion: T administration by the depot form of T-undecanoate can decrease carotid artery IMT as indicator of vascular damage in younger men. The effect is pronounced in overweight men with lower T concentrations. One may speculate that these effects are due to detrimental influences of T on pro-inflammatory substances and atherogenesis promoted by adipose tissue. doi:10.1016/j.jomh.2009.08.059
62 AGING MALES’ SYMPTOMS IN RELATION TO THE GENETICALLY DETERMINED ANDROGEN RECEPTOR CAG POLYMORPHISM, SEX HORMONE LEVELS AND SAMPLE MEMBERSHIP Michael Zitzmann 1,∗ , Kathrin Nienhaus 2 , Joerg Nieschlag 1 , Gudrun Schneider 2 1
Gromoll 1 , Gereon
Heuft 2 , Eberhard
University Clinics of Muenster, Germany, Centre for Reproductive Medicine and Androlgoy, Policlinics for Psychosomatics and Psychotherapy E-mail address: [email protected] (M. Zitzmann).
2
Clinic and
Background: ‘‘Late-onset hypogonadism’’ describes the co-occurrence of a range of physical, psychological and sexual symptoms in aging men., with the implication that these symptoms are caused by androgen deficiency. Previous investigations examined mostly population samples and did not take into account the testosterone modulating effects of the genetically determined CAG-repeat polymorphism (CAGn) of the androgen receptor (AR) gene. Methods: This is the first study which investigates aging male symptoms using the Aging Males Symptoms Scale (AMS) in relation to the genetically determined androgen receptor CAG polymorphism, estradiol and testosterone levels in > 50 years old men of a healthy population sample (n = 100), outpatients of an andrological department (n = 76) who presented because of sexual and ‘àging male’’ symptoms and a psychosomatic/psychiatric sample (n = 120) who presented because of various psychological and medically unexplained somatic complaints. Results: Although the population sample was significantly older than the two patient groups, they reported significantly fewer aging males symptoms and had higher testosterone levels and shorter CAG-repeats of the AR. The subgroup defined by the upper CAGn tercile and the lowest total testosterone tercile (lowest androgenicity) showed the highest level of aging male symptoms. Regression analysis revealed influences of CAGn and sample membership on the AMS global score and the psychological and somatic subscale, but not of testosterone. Longer CAGn and belonging to the psychosomatic or andrological sample were associated with a higher risk for AMS symptoms in regression analysis. Conclusion: Our results suggest that so-called aging male symptoms show a certain association to androgenicity, but that they are rather unspecific and of multifactorial origin. Other factors contributing to aging male symptoms need further clarification. doi:10.1016/j.jomh.2009.08.060
Aksam A. Yassin 1,2,∗ , Farid Saad 2,3 Segeberger Kliniken, Norderstedt-Hamburg, Germany, 2 Gulf Medical College School of Medicine, Ajman/UAE, 3 Bayer Schering Pharma AG, Scientific Affairs Men’s Healthcare, Berlin, Germany E-mail address: [email protected] (A.A. Yassin). Background: Obesity is an increasing worldwide epidemic. It is part of the metabolic syndrome, in addition to hypertension, insulin resistance and dyslipidemia, which predisposes to cardiovascular disease and diabetes. Increasingly, a role for testosterone is recognized in the metabolic syndrome. Methods: Review of the literature. Results: A large number of studies have documented that visceral obesity and diabetes are associated with low plasma total testosterone levels. A recent study demonstrated a positive correlation between serum testosterone levels and insulin sensitivity in men across the full spectrum of glucose tolerance. Men with prostate cancer, treated with androgen deprivation, develop an increase of fat mass, hyperinsulinemia, hyperglycemia, and insulin resistance. There is growing insight into the relationship between testosterone and adipose tissue. Testosterone regulates differentiation of mesenchymal pluripotent cells into either fat cells or muscle cells. From this it would follow that restoration of testosterone levels to normal would lead to an increase of muscle mass and a decrease of fat mass, which is the case. An increasing number of controlled as well as observational studies indicate that normalising testosterone levels in viscerally obese men leads to a reduction of visceral fat. Conclusion: Treatment of obesity is notoriously difficult. Testosterone may be a new treatment option for obese men with testosterone deficiency. doi:10.1016/j.jomh.2009.08.061
64 ANDROGEN DEPRIVATION THERAPY IN PATIENTS WITH ADVANCED PROSTATE CANCER AND TYPE 2 DIABETES IMPAIRS GLUCOSE AND LIPID METABOLISM A. Haider 1,∗ , A. Yassin 2,3 , R. Shabsigh 4 , F. Saad 2,5 1
Private Urology Practice, Bremerhaven, Germany, 2 Gulf Medical University School of Medicine, Ajman/UAE, 3 Institute of Urology and Andrology, Segeberger Kliniken, Norderstedt-Hamburg, Germany, 4 Maimonides Hospital and Columbia University, New York, USA, 5 Bayer Schering Pharma, Scientific Affairs Men’s Healthcare, Berlin, Germany E-mail address: [email protected] (A. Haider). Background: Treatment of prostate cancer with androgen deprivation therapy (ADT) has side effects such as bone loss, altered body composition and vascular complications. This study analyzed effects on glycemic control and lipid profiles in 29 men with insulin-dependent diabetes. Methods: 29 men were retrospectively analyzed. All men had preexistent insulin-dependent diabetes mellitus when they were diagnosed with advanced prostate cancer and consequently treated with GnRH analogs. Levels of fasting glucose, HbA1c, total cholesterol, HDL-C, LDL-C, triglycerides, fibrinogen, PAI-1, tPA, C-reactive protein as well as insulin requirement on 5 to 8 occasions (depending on survival time) over a period of up to 24 months were evaluated. Results: After 5 measurements (all 29 men), glycemic control worsened substantially with increases of serum glucose (from 143.2 to 187.3 mg/dL) requiring increases in insulin dosages (from 26.1 to 48.2 units). HbA1c levels rose from 6.3 % to 9.3 % indicating impaired glycemic control. All biochemical cardiovascular risk factors deteriorated: CRP from 1.3 to 2.3 mg/dL, total cholesterol from 252.0 to 322.3 mg/dL, HDL-C from 31.4 to 20.9 mg/dL, LDL-C from 184.5 to 229.1 mg/dL, triglycerides from 207.4 to 283.9 mg/dL, fibrinogen (data from n = 13) from 3.0 to 13.0 g/L, PAI-1 (data from n = 6) from 36.9 to 69.0 /L, and t-PA (data from n = 6) from 124.9 to 185.7 %. Conclusion: ADT has severely detrimental effects on glycemic control and lipid profiles in diabetics. These side effect require full attention and potentially preventive strategies. doi:10.1016/j.jomh.2009.08.062
jmh
Vol. 6, No. 3, pp. 229–275, September 2009
243
63
TESTOSTERONE ADMINISTRATION DECREASES CAROTID ARTERY INTIMA MEDIA THICKNESS AS A MARKER OF IMPAIRED VASCULAR INTEGRITY IN MIDDLE-AGED OVERWEIGHT MEN
TESTOSTERONE AND OBESITY — A REVIEW OF THE CURRENT LITERATURE
Michael Zitzmann 1,∗ , Elena Vorona 1 , Melanie Wenk 1 , Farid Saad 2 , Eberhard Nieschlag 1
1
Center for Reproductive Medicine and Andrology, University Clinics of Muenster, Germany, 2 Bayer Schering Pharma AG, Scientific Affairs Men’s Healthcare, Berlin, Germany, and Gulf Medical University, Ajman, UAE E-mail address: [email protected] (M. Zitzmann).
1
Background: Overweight in younger people is an increasing problem, being a clinically significant risk factor for the development of cardiovascular disease in later life. Epidemiological studies suggest that testosterone (T) deficiency in men is associated with the amount of adipose tissue and can augment its adverse effects, possibly by propagating the shedding of pro-inflammatory substances. These approaches focus on the presence of cardiovascular events in older men. In younger men, carotid artery intima media thickness (IMT) as an indicator of intravascular inflammation represents an early marker of subclinical vessel damage. We speculated whether the administration of a depot-form of T (intramuscular T-undecanoate) might have beneficial effects on IMT in younger overweight men. Methods: 42 middle-aged, healthy men were included in a body mass index (BMI)matched, controlled interventional study, receiving 4 intramuscular injections of 1000 mg of T-undecanoate in increasing intervals in weeks 0, 6, 14, 24. Group 1 (n = 21, 33.3 ± 7.7 years) had a BMI > 25 kg/m2 . Group 2 (controls, n = 21, 31.2 ± 6.2 years) had a BMI < 25 kg/m2 . Primary endpoint parameter was IMT, secondary endpoints were lipoprotein and triglyceride concentrations. Safety parameters were PSA and hematocrit. A classical threshold for androgen deficiency was not defined as an inclusion criterium. Results: Baseline characteristics were markedly different in Group 1 vs Group 2. Mean IMT was 0.86 ± 0.1 mm vs 0.75 ± 0,1 mm, p = 0.001; total T concentrations were12.6 ± 4.2nmol/L vs 16.2 ± 3.4nmol/L, p = 0.004, respectively. End-of-treatment assessments revealed IMT to be significantly decreased in Group 1 (0.63 ± 0.1 mm) as well as in Group 2 (0.59 ± 0.1 mm), p < 0.001 by paired t-tests for both groups, respectively. ANCOVA assessments for repeated measurements revealed the overall treatment effect to be augmented by lower baseline T levels (p = 0.002) and higher baseline BMI (p = 0.02). Corresponding alterations were seen in body composition. No significant changes in these healthy men were noted for lipoprotein concentrations, blood pressure, PSA or hematocrit. Conclusion: T administration by the depot form of T-undecanoate can decrease carotid artery IMT as indicator of vascular damage in younger men. The effect is pronounced in overweight men with lower T concentrations. One may speculate that these effects are due to detrimental influences of T on pro-inflammatory substances and atherogenesis promoted by adipose tissue. doi:10.1016/j.jomh.2009.08.059
62 AGING MALES’ SYMPTOMS IN RELATION TO THE GENETICALLY DETERMINED ANDROGEN RECEPTOR CAG POLYMORPHISM, SEX HORMONE LEVELS AND SAMPLE MEMBERSHIP Michael Zitzmann 1,∗ , Kathrin Nienhaus 2 , Joerg Nieschlag 1 , Gudrun Schneider 2 1
Gromoll 1 , Gereon
Heuft 2 , Eberhard
University Clinics of Muenster, Germany, Centre for Reproductive Medicine and Androlgoy, Policlinics for Psychosomatics and Psychotherapy E-mail address: [email protected] (M. Zitzmann).
2
Clinic and
Background: ‘‘Late-onset hypogonadism’’ describes the co-occurrence of a range of physical, psychological and sexual symptoms in aging men., with the implication that these symptoms are caused by androgen deficiency. Previous investigations examined mostly population samples and did not take into account the testosterone modulating effects of the genetically determined CAG-repeat polymorphism (CAGn) of the androgen receptor (AR) gene. Methods: This is the first study which investigates aging male symptoms using the Aging Males Symptoms Scale (AMS) in relation to the genetically determined androgen receptor CAG polymorphism, estradiol and testosterone levels in > 50 years old men of a healthy population sample (n = 100), outpatients of an andrological department (n = 76) who presented because of sexual and ‘àging male’’ symptoms and a psychosomatic/psychiatric sample (n = 120) who presented because of various psychological and medically unexplained somatic complaints. Results: Although the population sample was significantly older than the two patient groups, they reported significantly fewer aging males symptoms and had higher testosterone levels and shorter CAG-repeats of the AR. The subgroup defined by the upper CAGn tercile and the lowest total testosterone tercile (lowest androgenicity) showed the highest level of aging male symptoms. Regression analysis revealed influences of CAGn and sample membership on the AMS global score and the psychological and somatic subscale, but not of testosterone. Longer CAGn and belonging to the psychosomatic or andrological sample were associated with a higher risk for AMS symptoms in regression analysis. Conclusion: Our results suggest that so-called aging male symptoms show a certain association to androgenicity, but that they are rather unspecific and of multifactorial origin. Other factors contributing to aging male symptoms need further clarification. doi:10.1016/j.jomh.2009.08.060
Aksam A. Yassin 1,2,∗ , Farid Saad 2,3 Segeberger Kliniken, Norderstedt-Hamburg, Germany, 2 Gulf Medical College School of Medicine, Ajman/UAE, 3 Bayer Schering Pharma AG, Scientific Affairs Men’s Healthcare, Berlin, Germany E-mail address: [email protected] (A.A. Yassin). Background: Obesity is an increasing worldwide epidemic. It is part of the metabolic syndrome, in addition to hypertension, insulin resistance and dyslipidemia, which predisposes to cardiovascular disease and diabetes. Increasingly, a role for testosterone is recognized in the metabolic syndrome. Methods: Review of the literature. Results: A large number of studies have documented that visceral obesity and diabetes are associated with low plasma total testosterone levels. A recent study demonstrated a positive correlation between serum testosterone levels and insulin sensitivity in men across the full spectrum of glucose tolerance. Men with prostate cancer, treated with androgen deprivation, develop an increase of fat mass, hyperinsulinemia, hyperglycemia, and insulin resistance. There is growing insight into the relationship between testosterone and adipose tissue. Testosterone regulates differentiation of mesenchymal pluripotent cells into either fat cells or muscle cells. From this it would follow that restoration of testosterone levels to normal would lead to an increase of muscle mass and a decrease of fat mass, which is the case. An increasing number of controlled as well as observational studies indicate that normalising testosterone levels in viscerally obese men leads to a reduction of visceral fat. Conclusion: Treatment of obesity is notoriously difficult. Testosterone may be a new treatment option for obese men with testosterone deficiency. doi:10.1016/j.jomh.2009.08.061
64 ANDROGEN DEPRIVATION THERAPY IN PATIENTS WITH ADVANCED PROSTATE CANCER AND TYPE 2 DIABETES IMPAIRS GLUCOSE AND LIPID METABOLISM A. Haider 1,∗ , A. Yassin 2,3 , R. Shabsigh 4 , F. Saad 2,5 1
Private Urology Practice, Bremerhaven, Germany, 2 Gulf Medical University School of Medicine, Ajman/UAE, 3 Institute of Urology and Andrology, Segeberger Kliniken, Norderstedt-Hamburg, Germany, 4 Maimonides Hospital and Columbia University, New York, USA, 5 Bayer Schering Pharma, Scientific Affairs Men’s Healthcare, Berlin, Germany E-mail address: [email protected] (A. Haider). Background: Treatment of prostate cancer with androgen deprivation therapy (ADT) has side effects such as bone loss, altered body composition and vascular complications. This study analyzed effects on glycemic control and lipid profiles in 29 men with insulin-dependent diabetes. Methods: 29 men were retrospectively analyzed. All men had preexistent insulin-dependent diabetes mellitus when they were diagnosed with advanced prostate cancer and consequently treated with GnRH analogs. Levels of fasting glucose, HbA1c, total cholesterol, HDL-C, LDL-C, triglycerides, fibrinogen, PAI-1, tPA, C-reactive protein as well as insulin requirement on 5 to 8 occasions (depending on survival time) over a period of up to 24 months were evaluated. Results: After 5 measurements (all 29 men), glycemic control worsened substantially with increases of serum glucose (from 143.2 to 187.3 mg/dL) requiring increases in insulin dosages (from 26.1 to 48.2 units). HbA1c levels rose from 6.3 % to 9.3 % indicating impaired glycemic control. All biochemical cardiovascular risk factors deteriorated: CRP from 1.3 to 2.3 mg/dL, total cholesterol from 252.0 to 322.3 mg/dL, HDL-C from 31.4 to 20.9 mg/dL, LDL-C from 184.5 to 229.1 mg/dL, triglycerides from 207.4 to 283.9 mg/dL, fibrinogen (data from n = 13) from 3.0 to 13.0 g/L, PAI-1 (data from n = 6) from 36.9 to 69.0 /L, and t-PA (data from n = 6) from 124.9 to 185.7 %. Conclusion: ADT has severely detrimental effects on glycemic control and lipid profiles in diabetics. These side effect require full attention and potentially preventive strategies. doi:10.1016/j.jomh.2009.08.062
jmh
Vol. 6, No. 3, pp. 229–275, September 2009
243