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The aging male in Europe
Berzelius Symposium: Aging Male, Abstracts
Abstract: The Aging Male An aging world – challenges ahead B. Lunenfeld
B. Lunenfeld Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 52900, Israel
Over the past century, the world has seen enormous changes, including historically unprecedented declines in mortality rates and increases in population, followed by equally unprecedented declines in fertility rates. This century will see a new set of demographic challenges, including a mix of falling fertility rates alongside persisting worldwide population growth, and the subsequent aging of populations in both developing and developed countries. The 20th century was the century of population growth; the 21st century will go into the history books as the century of aging. Since the increase of life expectancy at birth did not parallel health expectancy, the rise in morbidity will increase the burden on national healthcare systems. Strategies decreasing, delaying or preventing lung, colon and prostate cancer in men and breast, ovarian
and endometrial cancer in women are being actively developed. Optimizing life styles to delay cardiovascular disease, the metabolic syndrome and various fractures are already promoted widely in many regions. Preventive strategies should increase health expectancy but will necessitate a quantum leap in multidisciplinary and internationally coordinated research efforts, supported by a new and fair partnership between industry and governments, philanthropic and international organizations. This collaboration we hope will enrich us with a better understanding of healthy aging, permit us to help to improve the quality of life, prevent the preventable, and postpone and decrease the pain and suffering of the inevitable. doi: 10.1016/j.jomh.2008.06.003
The male: historic and ontogenic aspects R.S. Swerdloff
R.S. Swerdloff Harbor-UCLA Medical Center, Los Angeles BioMedical Research Institute, David Geffen School of Medicine, Los Angeles, California, USA
F.C.W. Wu Department of Endocrinology/Medicine, University of Manchester, United Kingdom
A2
Testosterone levels provide a symphony of life in the male resulting in developmental, physiologic and pathophysiologic roles at different ages in man. Testosterone is responsible in the fetus for sexual differentiation of the gonads, internal and external genitalia and CNS. A surge of testosterone occurs in the neonatal period and this increase results in penile growth and may influence psychosexual development. Testosterone secretion diminishes during childhood only to rise again during puberty. The masculinizing effects at puberty and adulthood are demonstrated at many target levels including muscle, bone, fat, bone marrow, genitalia and brain. The latter effects are most obvious for libido but also produce gender selective effects on neurocognitive function. Testosterone reaches its peak by the age of 30 years and falls in a near linear fashion with progressive aging. Testosterone levels in the
elderly often reach concentrations below the reference range for a normal young adult male and are associated with hypogonadal symptoms. Testosterone is important for normal erectile function with actions occurring at the CNS and penile levels. Testosterone deficiency is associated with increased cardiovascular risk. Testosterone levels are reduced in acute and chronic illness including diabetes mellitus. Low serum testosterone appears to anticipate the metabolic syndrome and increased risk of diabetes mellitus type 2. Testosterone may also be a growth factor for hormone responsive tumors such as prostate cancer. The recognition of these growth stimulating effects on prostate and breast cancer leads to therapeutic interventions with medical or surgical castration reducing the growth of the neoplasm. doi: 10.1016/j.jomh.2008.06.004
The aging male in Europe F.C.W. Wu
The relationships between alterations in hormones in ageing men with the clinical features of senescence remain unclear. One fruitful
Vol. 5, No. 3, pp. A2–A19, September 2008
area of study is to investigate the natural history and any risk factors associated with potential adverse consequences associated
Berzelius Symposium: Aging Male, Abstracts with low testosterone in a general population of ageing men. The European Male Ageing Study (EMAS) is a population-based prospective cohort study of 3369 men (aged 40–79 yr) from the general population of 8 European countries. A wide variety of relevant clinical variables pertinent to general, sexual, physical and mental health are documented together with biochemical, hormonal and genetic markers. The baseline cross-sectional data related to general and sexual health across Europe, late onset or I.T. Huhtaniemi Imperial College London, UK S.R. Pye, K.L. Limer, W. Thomson, T.W. O’Neill, H. Platt, D. Payne, S.L. John, J.E. Adams, K.A. Ward, J.D. Finn, A.J. Silman, F.C.W. Wu University of Manchester, UK M. Jiang, A. Perheentupa University of Turku, Finland S. Boonen, H. Borghs, D. Vanderschueren, University of Leuven, Belgium G. Bartfai University of Szeged, Hungary F. Casanueva University of Santiago de Compostela, Spain G. Forti University of Florence, Italy A. Giwercman Reproductive Medicine Center, Lund University, Sweden T.S. Han University College London, UK K. Kula University of Lodz, Poland M.E.J. Lean, N. Pendleton University of Glasgow, UK M. Punab University of Tartu, Estonia the TuMAS and EMAS Study Groups
sub-clinical hypogonadism, frailty index and bone health and their relationship to testosterone and testosterone action will be presented. These data show that changes in many domains of health in ageing men are only weakly associated with alterations in hormone function. The concept of a syndrome of hypogonadism of ageing may only be applicable to a small minority of men in the general population. doi: 10.1016/j.jomh.2008.06.005
Genetic aspects in the gender-specific aging of men I.T. Huhtaniemi
Testicular endocrine function, and the anabolic, psychological and sexual functions maintained by testosterone (T) are known to decline with age. These alterations are proposed to form the functional basis of the male gender specific phenomena of ageing. A novel syndrome, late onset hypogonadism (LOH), has been proposed for the symptomatic decline of T production with ageing. However, the high score of LOH symptoms and low T seldom coincide in ageing men which prompts us to question the real importance of T decrease for the health and quality of life of ageing men. We report here findings of two studies exploring male ageing, The European Male Ageing Study (EMAS) and The Turku Male Ageing Study (TuMAS). They are prospective (EMAS) and crossectional (TuMAS) random general population cohort studies aimed at identifying the interplay between genetic and environmental risk factors which predispose to symptoms, disabilities and diseases associated with ageing in men. A total of 3,200 men between the ages of 40–79 yr were recruited in 8 European centres (Belgium, Estonia, Hungary, Italy, Poland, Spain, Sweden, UK) for EMAS, and 15,500 men of 41–70 yr from Turku, Finland, for TuMAS. A comprehensive data base on health status and various signs and symptoms related to LOH, including anthropometric, biochemical and endocrine measurements, were collected from the men. We have also genotyped various subsets of the men from each country for polymorphisms in 12 sex hormone-related candidate genes to explore their genetic variation across Europe and to test for associations with phenotypic endpoints such as hormones, lipids, body mass index and bone mass. The candidate genes
selected for the analysis were AR, CYP17, CYP19, ERa, ERß, IGF-1, LHß, LHCGR, NPY, SHBG, SRD5A2 and VDR. Altogether 77 SNPs were selected using literature and public database resources amongst those previously shown associations with hormone levels or cardiovascular traits, and mainly located in exonic or regulatory regions of the genes. Amongst the findings, a single SNP in the promoter region of SHBG was associated with total and free T, sex hormone-binding globulin (SHBG), oestradiol (E2) and LH levels. Several intronic and exonic SNPs in CYP19 were associated with E2 and free T levels. An exonic SNP in ERa was associated with free T and two additional SNPs with LH. Two intronic SNPs in IGF-1 were associated with serum FSH. The CAG repeat length in exon 1 of AR was directly associated with serum levels of total, free and bioavailable T and E2. Likewise several indicators of bone density were directly associated with the AR CAG repeat length, but no correlation of the repeat length with a variety of androgendependent clinical and biochemical endpoints was observed. Hence, in contrast to many previous findings, increased oestrogen, rather than suppressed androgen action, was found to be associated with increased AR CAG repeat length. Due to the relatively homogeneous genetic background and similarity of the endocrine alterations, we can conclude that environmental rather than genetic factors are the most significant determinant of the health status and its regional differences in European men. Supported by grants from the European Union and the Academy of Finland. doi: 10.1016/j.jomh.2008.06.006
Vol. 5, No. 3, pp. A2–A19, September 2008
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Abstract: The Aging Male An aging world – challenges ahead B. Lunenfeld
B. Lunenfeld Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 52900, Israel
Over the past century, the world has seen enormous changes, including historically unprecedented declines in mortality rates and increases in population, followed by equally unprecedented declines in fertility rates. This century will see a new set of demographic challenges, including a mix of falling fertility rates alongside persisting worldwide population growth, and the subsequent aging of populations in both developing and developed countries. The 20th century was the century of population growth; the 21st century will go into the history books as the century of aging. Since the increase of life expectancy at birth did not parallel health expectancy, the rise in morbidity will increase the burden on national healthcare systems. Strategies decreasing, delaying or preventing lung, colon and prostate cancer in men and breast, ovarian
and endometrial cancer in women are being actively developed. Optimizing life styles to delay cardiovascular disease, the metabolic syndrome and various fractures are already promoted widely in many regions. Preventive strategies should increase health expectancy but will necessitate a quantum leap in multidisciplinary and internationally coordinated research efforts, supported by a new and fair partnership between industry and governments, philanthropic and international organizations. This collaboration we hope will enrich us with a better understanding of healthy aging, permit us to help to improve the quality of life, prevent the preventable, and postpone and decrease the pain and suffering of the inevitable. doi: 10.1016/j.jomh.2008.06.003
The male: historic and ontogenic aspects R.S. Swerdloff
R.S. Swerdloff Harbor-UCLA Medical Center, Los Angeles BioMedical Research Institute, David Geffen School of Medicine, Los Angeles, California, USA
F.C.W. Wu Department of Endocrinology/Medicine, University of Manchester, United Kingdom
A2
Testosterone levels provide a symphony of life in the male resulting in developmental, physiologic and pathophysiologic roles at different ages in man. Testosterone is responsible in the fetus for sexual differentiation of the gonads, internal and external genitalia and CNS. A surge of testosterone occurs in the neonatal period and this increase results in penile growth and may influence psychosexual development. Testosterone secretion diminishes during childhood only to rise again during puberty. The masculinizing effects at puberty and adulthood are demonstrated at many target levels including muscle, bone, fat, bone marrow, genitalia and brain. The latter effects are most obvious for libido but also produce gender selective effects on neurocognitive function. Testosterone reaches its peak by the age of 30 years and falls in a near linear fashion with progressive aging. Testosterone levels in the
elderly often reach concentrations below the reference range for a normal young adult male and are associated with hypogonadal symptoms. Testosterone is important for normal erectile function with actions occurring at the CNS and penile levels. Testosterone deficiency is associated with increased cardiovascular risk. Testosterone levels are reduced in acute and chronic illness including diabetes mellitus. Low serum testosterone appears to anticipate the metabolic syndrome and increased risk of diabetes mellitus type 2. Testosterone may also be a growth factor for hormone responsive tumors such as prostate cancer. The recognition of these growth stimulating effects on prostate and breast cancer leads to therapeutic interventions with medical or surgical castration reducing the growth of the neoplasm. doi: 10.1016/j.jomh.2008.06.004
The aging male in Europe F.C.W. Wu
The relationships between alterations in hormones in ageing men with the clinical features of senescence remain unclear. One fruitful
Vol. 5, No. 3, pp. A2–A19, September 2008
area of study is to investigate the natural history and any risk factors associated with potential adverse consequences associated
Berzelius Symposium: Aging Male, Abstracts with low testosterone in a general population of ageing men. The European Male Ageing Study (EMAS) is a population-based prospective cohort study of 3369 men (aged 40–79 yr) from the general population of 8 European countries. A wide variety of relevant clinical variables pertinent to general, sexual, physical and mental health are documented together with biochemical, hormonal and genetic markers. The baseline cross-sectional data related to general and sexual health across Europe, late onset or I.T. Huhtaniemi Imperial College London, UK S.R. Pye, K.L. Limer, W. Thomson, T.W. O’Neill, H. Platt, D. Payne, S.L. John, J.E. Adams, K.A. Ward, J.D. Finn, A.J. Silman, F.C.W. Wu University of Manchester, UK M. Jiang, A. Perheentupa University of Turku, Finland S. Boonen, H. Borghs, D. Vanderschueren, University of Leuven, Belgium G. Bartfai University of Szeged, Hungary F. Casanueva University of Santiago de Compostela, Spain G. Forti University of Florence, Italy A. Giwercman Reproductive Medicine Center, Lund University, Sweden T.S. Han University College London, UK K. Kula University of Lodz, Poland M.E.J. Lean, N. Pendleton University of Glasgow, UK M. Punab University of Tartu, Estonia the TuMAS and EMAS Study Groups
sub-clinical hypogonadism, frailty index and bone health and their relationship to testosterone and testosterone action will be presented. These data show that changes in many domains of health in ageing men are only weakly associated with alterations in hormone function. The concept of a syndrome of hypogonadism of ageing may only be applicable to a small minority of men in the general population. doi: 10.1016/j.jomh.2008.06.005
Genetic aspects in the gender-specific aging of men I.T. Huhtaniemi
Testicular endocrine function, and the anabolic, psychological and sexual functions maintained by testosterone (T) are known to decline with age. These alterations are proposed to form the functional basis of the male gender specific phenomena of ageing. A novel syndrome, late onset hypogonadism (LOH), has been proposed for the symptomatic decline of T production with ageing. However, the high score of LOH symptoms and low T seldom coincide in ageing men which prompts us to question the real importance of T decrease for the health and quality of life of ageing men. We report here findings of two studies exploring male ageing, The European Male Ageing Study (EMAS) and The Turku Male Ageing Study (TuMAS). They are prospective (EMAS) and crossectional (TuMAS) random general population cohort studies aimed at identifying the interplay between genetic and environmental risk factors which predispose to symptoms, disabilities and diseases associated with ageing in men. A total of 3,200 men between the ages of 40–79 yr were recruited in 8 European centres (Belgium, Estonia, Hungary, Italy, Poland, Spain, Sweden, UK) for EMAS, and 15,500 men of 41–70 yr from Turku, Finland, for TuMAS. A comprehensive data base on health status and various signs and symptoms related to LOH, including anthropometric, biochemical and endocrine measurements, were collected from the men. We have also genotyped various subsets of the men from each country for polymorphisms in 12 sex hormone-related candidate genes to explore their genetic variation across Europe and to test for associations with phenotypic endpoints such as hormones, lipids, body mass index and bone mass. The candidate genes
selected for the analysis were AR, CYP17, CYP19, ERa, ERß, IGF-1, LHß, LHCGR, NPY, SHBG, SRD5A2 and VDR. Altogether 77 SNPs were selected using literature and public database resources amongst those previously shown associations with hormone levels or cardiovascular traits, and mainly located in exonic or regulatory regions of the genes. Amongst the findings, a single SNP in the promoter region of SHBG was associated with total and free T, sex hormone-binding globulin (SHBG), oestradiol (E2) and LH levels. Several intronic and exonic SNPs in CYP19 were associated with E2 and free T levels. An exonic SNP in ERa was associated with free T and two additional SNPs with LH. Two intronic SNPs in IGF-1 were associated with serum FSH. The CAG repeat length in exon 1 of AR was directly associated with serum levels of total, free and bioavailable T and E2. Likewise several indicators of bone density were directly associated with the AR CAG repeat length, but no correlation of the repeat length with a variety of androgendependent clinical and biochemical endpoints was observed. Hence, in contrast to many previous findings, increased oestrogen, rather than suppressed androgen action, was found to be associated with increased AR CAG repeat length. Due to the relatively homogeneous genetic background and similarity of the endocrine alterations, we can conclude that environmental rather than genetic factors are the most significant determinant of the health status and its regional differences in European men. Supported by grants from the European Union and the Academy of Finland. doi: 10.1016/j.jomh.2008.06.006
Vol. 5, No. 3, pp. A2–A19, September 2008
A3