Krzysztof Kula

Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: The European Male Aging Study

CONTEXT The cause of declining testosterone (T) in aging men and their relationships with risk factors are unclear. OBJECTIVE The objective of the study was to investigate the relationships between lifestyle and health with reproductive hormones in aging men. DESIGN This was a baseline cross-sectional survey on 3200 community-dwelling men aged 40-79 yr from a prospective cohort study in eight European countries. RESULTS Four predictors were associated with distinct modes of altered function: 1) age: lower free T (FT; -3.12 pmol/liter.yr, P < 0.001) with raised LH, suggesting impaired testicular function; 2) obesity: lower total T (TT; -2.32 nmol/liter) and FT (-17.60 pmol/liter) for body mass index (BMI; > or = 25 to < 30 kg/m(2)) and lower TT (-5.09 nmol/liter) and FT (-53.72 pmol/liter) for BMI 30 kg/m(2) or greater (P < 0.001-0.01, referent: BMI < 25 kg/m(2)) with unchanged/decreased LH, indicating hypothalamus/pituitary dysfunction; 3) comorbidity: lower TT (-0.80 nmol/liter, P < 0.01) with unchanged LH in younger men but higher LH in older men; and 4) smoking: higher SHBG (5.96 nmol/liter, P < 0.001) and LH (0.77 U/liter, P < 0.01) with increased TT (1.31 nmol/liter, P < 0.001) but not FT, compatible with a resetting of T-LH-negative feedback due to elevated SHBG. CONCLUSIONS Complex multiple alterations in the hypothalamic-pituitary-testicular axis function exist in aging men against a background of progressive age-related testicular impairment. These changes are differentially linked to specific risk factors. Some risk factors operate independently of but others interact with age, in contributing to the T decline. These potentially modifiable risk factors suggest possible preventative measures to maintain T during aging in men.

Characteristics of Secondary, Primary, and Compensated Hypogonadism in Aging Men: Evidence from the European Male Ageing Study

CONTEXT The diagnosis of late-onset hypogonadism (LOH) in older men with age-related declines in testosterone (T) is currently not well characterized. OBJECTIVE Our objective was to investigate whether different forms of hypogonadism can be distinguished among aging men. DESIGN The study was a cross-sectional survey on 3369 community-dwelling men aged 40-79 yr in eight European centers. METHODS Four groups of subjects were defined: eugonadal (normal T and normal LH), secondary (low T and low/normal LH), primary (low T and elevated LH), and compensated (normal T and elevated LH) hypogonadism. Relationships between the defined gonadal status with potential risk factors and clinical symptoms were investigated by multilevel regression models. RESULTS Among the men, 11.8, 2.0, and 9.5% were classified into the secondary, primary, and compensated hypogonadism categories, respectively. Older men were more likely to have primary [relative risk ratio (RRR) = 3.04; P < 0.001] and compensated (RRR = 2.41; P < 0.001) hypogonadism. Body mass index of 30 kg/m(2) or higher was associated with secondary hypogonadism (RRR = 8.74; P < 0.001). Comorbidity was associated with both secondary and primary hypogonadism. Sexual symptoms were more prevalent in secondary and primary hypogonadism, whereas physical symptoms were more likely in compensated hypogonadism. CONCLUSIONS Symptomatic elderly men considered to have LOH can be differentiated on the basis of endocrine and clinical features and predisposing risk factors. Secondary hypogonadism is associated with obesity and primary hypogonadism predominately with age. Compensated hypogonadism can be considered a distinct clinical state associated with aging. Classification of LOH into different categories by combining LH with T may improve the diagnosis and management of LOH.

Age‐Related Changes in General and Sexual Health in Middle‐Aged and Older Men: Results from the European Male Ageing Study (EMAS)

INTRODUCTION Limited information is available concerning the general and sexual health status of European men. AIM To investigate the age-related changes in general and sexual health in middle-aged and older men from different countries of the European Union. METHODS This is a cross-sectional multicenter survey performed on a sample of 3,369 community-dwelling men aged 40-79 years old (mean 60 + or - 11 years). Subjects were randomly selected from eight European centers including centers from nontransitional (Florence [Italy], Leuven [Belgium], Malmö[Sweden], Manchester [United Kingdom], Santiago de Compostela [Spain]) and transitional countries (Lodz [Poland], Szeged [Hungary], Tartu [Estonia]). MAIN OUTCOME MEASURES Different parameters were evaluated including the Becks Depression Inventory for the quantification of depressive symptoms, the Short Form-36 Health Survey for the assessment of the quality of life (QoL), the International Prostate Symptom Score for the evaluation of lower urinary tract symptoms, and the European Male Ageing Study sexual function questionnaire for the study of sexual function. RESULTS More than 50% of subjects reported the presence of one or more common morbidities. Overall, hypertension (29%), obesity (24%), and heart diseases (16%) were the most prevalent conditions. Around 30% of men reported erectile dysfunction (ED) and 6% reported severe orgasmic impairment, both of which were closely associated with age and concomitant morbidities. Only 38% of men reporting ED were concerned about it. Furthermore, concern about ED increased with age, peaking in the 50-59 years age band, but decreased thereafter. Men in transitional countries reported a higher prevalence of morbidities and impairment of sexual function as well as a lower QoL. CONCLUSION Sexual health declined while concomitant morbidities increased in European men as a function of age. The burden of general and sexual health is higher in transitional countries, emphasizing the need to develop more effective strategies to promote healthy aging for men in these countries.

Characteristics of Androgen Deficiency in Late-Onset Hypogonadism: Results from the European Male Aging Study (EMAS).

CONTEXT Late-onset hypogonadism (LOH) has been defined as a syndrome in middle-aged and elderly men reporting symptoms in the presence of low testosterone (T). OBJECTIVE The objective of the study was to seek objective biochemical and end-organ evidence of androgen deficiency in men classified as having LOH according to our previously published criteria. DESIGN, SETTING, AND PARTICIPANTS The design of the study included cross-sectional data from the European Male Aging Study on 2966 community-dwelling men aged 40-79 years in eight European countries. MAIN OUTCOME MEASURE(S) Waist circumference, body mass index, muscle mass, estimated heel bone mineral density (eBMD), hemoglobin, insulin sensitivity, physical activity, metabolic syndrome, insulin resistance index, and cardiovascular disease were measured. RESULTS Sixty-three men (2.1%) were classified as having LOH: 36 moderate and 27 severe. They were older and more obese than eugonadal men and had, in proportion to the graded T deficiency, lower muscle mass, eBMD, and hemoglobin, with poorer general health. Both moderate and severe LOH was associated with lower hemoglobin, mid-upper arm circumference, eBMD, physical function (measured by the Short Form-36 questionnaire), slower gait speed and poorer general health. Only men with severe LOH showed significant associations with larger waist circumference (β=1.93 cm; 0.04-3.81), insulin resistance (β=2.81; 1.39-4.23), and the metabolic syndrome (odds ratio 9.94; 2.73-36.22) after adjustments for confounders. Men with low testosterone only (irrespective of symptoms) showed lesser magnitudes of association with the same end points. CONCLUSIONS LOH is associated with multiple end-organ deficits compatible with androgen deficiency. These data support the existence of a syndrome of LOH in only a minority of aging men, especially those with T below 8 nmol/liter.

Age-associated changes in hypothalamic-pituitary-testicular function in middle-aged and older men are modified by weight change and lifestyle factors: longitudinal results from the European Male Ageing Study.

OBJECTIVE Health and lifestyle factors are associated with variations in serum testosterone levels in ageing men. However, it remains unclear how age-related changes in testosterone may be attenuated by lifestyle modifications. The objective was to investigate the longitudinal relationships between changes in health and lifestyle factors with changes in hormones of the reproductive endocrine axis in ageing men. DESIGN A longitudinal survey of 2736 community-dwelling men aged 40-79 years at baseline recruited from eight centres across Europe. Follow-up assessment occurred mean (±S.D.) 4.4±0.3 years later. RESULTS Paired testosterone results were available for 2395 men. Mean (±S.D.) annualised hormone changes were as follows: testosterone -0.1±0.95  nmol/l; free testosterone (FT) -3.83±16.8  pmol/l; sex hormone-binding globulin (SHBG) 0.56±2.5  nmol/l and LH 0.08±0.57  U/l. Weight loss was associated with a proportional increase, and weight gain a proportional decrease, in testosterone and SHBG. FT showed a curvilinear relationship to weight change; only those who gained or lost ≥15% of weight showed a significant change (in the same direction as testosterone). Smoking cessation was associated with a greater decline in testosterone than being a non-smoker, which was unrelated to weight change. Changes in number of comorbid conditions or physical activity were not associated with significant alterations in hypothalamic-pituitary-testicular (HPT) axis function. CONCLUSIONS Body weight and lifestyle factors influence HPT axis function in ageing. Weight loss was associated with a rise, and weight gain a fall, in testosterone, FT and SHBG. Weight management appears to be important in maintaining circulating testosterone in ageing men, and obesity-associated changes in HPT axis hormones are reversible following weight reduction.

Association between 25-hydroxyvitamin D levels and cognitive performance in middle-aged and older European men

Background: Although there is evidence that vitamin D inadequacy may be linked to adverse cognitive outcomes, results from studies on this topic have been inconsistent. The aim of this trial was to examine the association between 25-hydroxyvitamin D (25(OH)D) levels and cognitive performance in middle-aged and older European men. Methods: This population-based cross-sectional study included 3,369 men aged 40–79 years from eight centres enrolled in the European Male Ageing Study. Cognitive function was assessed using the Rey–Osterrieth Complex Figure (ROCF) test, the Camden Topographical Recognition Memory (CTRM) test and the Digit Symbol Substitution Test (DSST). Serum 25(OH)D levels were measured by radioimmunoassay. Additional assessments included measurement of physical activity, functional performance and mood/depression. Associations between cognitive function and 25(OH)D levels were explored using locally weighted and linear regression models. Results: In total, 3,133 men (mean (±SD) age 60±11 years) were included in the analysis. The mean (±SD) 25(OH)D concentration was 63±31 nmol/l. In age-adjusted linear regressions, high levels of 25(OH)D were associated with high scores on the copy component of the ROCF test (β per 10 nmol/l = 0.096; 95% CI 0.049 to 0.144), the CTRM test (β per 10 nmol/l = 0.075; 95% CI 0.026 to 0.124) and the DSST (β per 10 nmol/l = 0.318; 95% CI 0.235 to 0.401). After adjusting for additional confounders, 25(OH)D levels were associated with only score on the DSST (β per 10 nmol/l = 0.152; 95% CI 0.051 to 0.253). Locally weighted and spline regressions suggested the relationship between 25(OH)D concentration and cognitive function was most pronounced at 25(OH)D concentrations below 35 nmol/l. Conclusion: In this study, lower 25(OH)D levels were associated with poorer performance on the DSST. Further research is warranted to determine whether vitamin D sufficiency might have a role in preserving cognitive function in older adults.

The European Male Ageing Study (EMAS): design, methods and recruitment

Life expectancy is increasing in most developed countries, in part due to improved socioeconomic conditions and in part to advances in healthcare. It is widely acknowledged that the promotion of healthy ageing by delaying, minimizing or preventing disabilities or diseases is one of the most important public health objectives in this century. In contrast to the menopausal transition in females, we know relatively little about the contribution of androgens and anabolic hormones to the quality of ageing in men. The European Male Ageing Study (EMAS) is a multicentre prospective cohort designed to examine the prevalence, incidence and geographical distribution of gender-specific and general symptoms of ageing in men, including their endocrine, genetic and psychosocial predictors. Men aged 40-79 years were recruited from eight European centres: Florence (Italy), Leuven (Belgium), Lodz (Poland), Malmö (Sweden), Manchester (UK), Santiago de Compostela (Spain), Szeged (Hungary) and Tartu (Estonia). Subjects were recruited from population registers and those who agreed to take part completed a detailed questionnaire including aspects of personal and medical history, lifestyle factors and sexual function. Objective measures of body size, cognition, vision, skeletal health and neuromuscular function were obtained. Blood and DNA specimens were collected for a range of biochemical and genetic analyses. After an average of 4 years, it is planned to resurvey the participants with similar assessments. A total of 3369 men with a mean age of 60 +/- 11 years were recruited. The mean centre response rate was 43%, and highest in those aged 50-59 years. Those who participated were marginally younger than those who were invited but declined to participate (60.0 vs. 61.1 years). Participants left education slightly later than a sample of non-participants, though there were no consistent differences in levels of general health, physical activity, or smoking. EMAS will provide new population-based data concerning the main features that characterize ageing in men and its critical determinants, particularly with reference to age-related changes in hormone levels. Such information is an important prerequisite to develop effective strategies to reduce age-related disabilities and optimise health and well-being into old-age.

Increased Estrogen Rather Than Decreased Androgen Action Is Associated with Longer Androgen Receptor CAG Repeats.

CONTEXT The individual variability in the waning androgenic-anabolic functions of aging men may be influenced by the CAG repeat polymorphism in exon 1 of the androgen receptor (AR), affecting androgen sensitivity. However, findings on its phenotypic effects are inconclusive. OBJECTIVE The aim was to investigate the relationships between health status, various reproductive hormones, and the AR CAG repeat length. DESIGN We conducted a multinational prospective cohort observational study with cross-sectional baseline data. SETTING This was a population survey of community-dwelling men. PARTICIPANTS Men (40-79 yr old; n = 3369) were randomly recruited from centers in eight European countries; CAG repeat analysis was performed in 2878 men. MAIN OUTCOME MEASURES We measured the correlations of the CAG repeat length with selected endocrine, metabolic, and phenotypic parameters related to aging and sex hormone action. RESULTS Only minor differences were found in CAG repeat lengths between the eight European countries. They showed significant positive association with total, free, and bioavailable levels of testosterone (T) and estradiol. FSH but not LH correlated inversely with CAG repeat length. Significant associations were found with bone ultrasound parameters at the calcaneus. Negative correlation was found with triglycerides, but not with other blood lipids or with anthropometry, blood pressure, hemoglobin, insulin sensitivity, or sexual and prostatic functions. CONCLUSIONS The AR CAG repeat length correlates significantly with serum T and estradiol of aging men. Weaker transcriptional activity of the AR with longer CAG-encoded polyglutamine repeats appears to be totally or nearly totally compensated for by higher T levels. The residual phenotypic correlations may reflect differences in estrogen levels/actions after aromatization of the higher T levels.

Late-onset hypogonadism and mortality in aging men.

CONTEXT Late-onset hypogonadism (LOH) has recently been defined as a syndrome in middle-aged and elderly men reporting sexual symptoms in the presence of low T. The natural history of LOH, especially its relationship to mortality, is currently unknown. OBJECTIVE The aim of this study was to clarify the associations between LOH, low T, and sexual symptoms with mortality in men. DESIGN, SETTING, AND PARTICIPANTS Prospective data from the European Male Aging Study (EMAS) on 2599 community-dwelling men aged 40-79 years in eight European countries was used for this study. MAIN OUTCOME MEASURE(S) All-cause, cardiovascular, and cancer-related mortality was measured. RESULTS One hundred forty-seven men died during a median follow-up of 4.3 years. Fifty-five men (2.1%) were identified as having LOH (31 moderate and 24 severe). After adjusting for age, center, body mass index (BMI), current smoking, and poor general health, compared with men without LOH, those with severe LOH had a 5-fold [hazard ratio (HR) 5.5; 95% confidence interval (CI) 2.7, 11.4] higher risk of all-cause mortality. Compared with eugonadal men, the multivariable-adjusted risk of mortality was 2-fold higher in those with T less than 8 nmol/L (irrespective of symptoms; HR 2.3; 95% CI 1.2, 4.2) and 3-fold higher in those with three sexual symptoms (irrespective of serum T; compared with asymptomatic men; HR 3.2; 95% CI 1.8, 5.8). Similar risks were observed for cardiovascular mortality. CONCLUSIONS Severe LOH is associated with substantially higher risks of all-cause and cardiovascular mortality, to which both the level of T and the presence of sexual symptoms contribute independently. Detecting low T in men presenting with sexual symptoms offers an opportunity to identify a small subgroup of aging men at particularly high risk of dying.

Comparison of serum testosterone and estradiol measurements in 3174 European men using platform immunoassay and mass spectrometry; relevance for the diagnostics in aging men.

BACKGROUND The limitations of serum testosterone and estradiol (E(2)) measurements using non-extraction platform immunoassays (IAs) are widely recognized. Switching to more specific mass spectrometry (MS)-based methods has been advocated, but directly comparative data on the two methods are scarce. METHODS We compared serum testosterone and E(2) measurements in a large sample of middle-aged/elderly men using a common platform IA and a gas chromatography (GC)-MS method, in order to assess their limitations and advantages, and to diagnose male hypogonadism. Of subjects from the European Male Aging Study (n=3174; age 40-79 years), peripheral serum testosterone and E(2) were analyzed using established commercial platform IAs (Roche Diagnostics E170) and in-house GC-MS methods. RESULTS Over a broad concentration range, serum testosterone concentration measured by IA and MS showed high correlation (R=0.93, P<0.001), which was less robust in the hypogonadal range (<11 nmol/l; R=0.72, P<0.001). The IA/MS correlation was weaker in E(2) measurements (R=0.32, P<0.001, at E(2) <40.8 pmol/l, and R=0.74, P<0.001, at E(2) >40.8 pmol/l). Using MS as the comparator method, IA ascertained low testosterone compatible with hypogonadism (<11 nmol/l), with 75% sensitivity and 96.3% specificity. The same parameters with IA for the detection of low E(2) (<40.7 pmol/l) were 13.3 and 99.3%, and for high E(2) (>120 pmol/l) 88.4 and 88.6%. CONCLUSION A validated platform IA is sufficient to detect subnormal testosterone concentrations in the diagnosis of male hypogonadism. The IA used for E(2) measurements showed poor correlation with MS and may only be suitable for the detection of high E(2) in men.