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Free access

Jakob Eberhard, Olof Ståhl, Magdalena Cwikiel, Eva Cavallin-Ståhl, Yvonne Giwercman, Eva Cecilia Salmonson, and Aleksander Giwercman

Objectives

Testicular germ-cell cancer (TGCC) patients are at risk of developing hypogonadism but no risk factors have yet been defined.

Methods

Blood was collected from 143 TGCC patients (after orchidectomy, prior to further therapy (T0) and 6, 12, 24, 36 and 60 months (T6, T12, T24, T36 and T60) after therapy). Biological hypogonadism (BH) was defined as: serum testosterone below 10 nmol/l and/or LH >10 IU/l; odds ratios (ORs) for BH with BH at T0, age, stage of disease, testicular characteristics, and androgen receptor polymorphism as predictors were calculated as well as the OR for developing BH post-treatment (one to two cycles of adjuvant chemotherapy (ACT) versus three to four cycles of higher dose chemotherapy (HCT) versus adjuvant radiotherapy (RT)).

Results

HCT increased the OR for BH at T6 (OR 22, 95% confidence interval (CI) 4.4–118) and T12 (OR 5.8, 95% CI 1.5–22). RT increased the OR at T6 (OR 10, 95% CI 2.1–47) and at T12 (OR 3.9, 95% CI 1.1–14). Microlithiasis predicted BH at T0 (OR 11, 95% CI 1.2–112), T12 (OR 3.9, 95% CI 1.1–13), T24 (OR 3.0, 95% CI 1.0–8.8), T36 (OR 5.4, 95% CI 1.7–17) and T60 (OR 4.4, 95% CI 1.2–16). BH at T0 was a risk for BH at T6 (OR 53, 95% CI 19–145), T12 (OR 125, 95% CI 37–430), T24 (OR 88, 95% CI 26–300) and T36 (OR 121, 95% CI 32–460).

Conclusions

It is clinically relevant that BH at T0 and testicular microlithiasis were predictive factors for post-treatment BH. HCT and RT gave temporary BH.

Open access

Angel Elenkov, Yahia Al-Jebari, Yvonne Lundberg Giwercman, and Aleksander Giwercman

Objectives

Male hypogonadism is associated with higher risk of co-morbidity and premature mortality. It is, therefore, of utmost importance to identify young men who are at the highest risk of testosterone deficiency and who may benefit from preventive measures. In this context, infertile men constitute a high-risk group. The extent of testosterone replacement therapy (TRT) among infertile men, defined as men who have to undergo assisted reproduction for fatherhood, is currently unknown. Therefore, we evaluated the pattern of prescription of TRT in the years following child conception among men who have fathered children with the help of intracytoplasmic sperm injection (ICSI) or in vitro fertilization (IVF).

Design

By sourcing data from national population registries, hazard ratio (HR) for subsequent TRT was assessed for IVF and ICSI-treated men and compared to those who conceived spontaneously with age Cox regression analysis adjusted for age, educational level and previous intake of medicines for metabolic diseases.

Results

ICSI and IVF fathers had increased incidence of newly prescribed TRT compared to fathers conceiving spontaneously (ICSI: HR = 3.81, 95% CI = 3.09–4.69, P < 0.001; IVF: HR = 1.54, 95% CI = 1.15–2.05, P = 0.003). After adjustment for prescription of medication for one or more components of the MetS prior to TRT, the risk estimates attenuated but remained robust both for ICSI-treated (HR = 3.17 (95% CI: 2.56–3.9) and IVF-treated men (HR = 1.06 (95% CI: 1.05–1.07).

Conclusion

Men who have to utilise powerful techniques, such as ICSI for fathering children, may be at risk for testosterone deficiency. Routine endocrine evaluation of men seeking fertility treatment is hence warranted.

Restricted access

Axel Netterlid, Helena Mörse, Aleksander Giwercman, Emir Henic, Kristina E Akesson, Eva Marie Erfurth, and Maria Elfving

Objective: Female childhood cancer survivors (CCS) are at risk of several late effects, among them metabolic syndrome (MetS) and premature ovarian insufficiency (POI). The objective is to study if POI is associated with risk of MetS and increased cardiovascular risk in CSS.

Design: A cross-sectional study with a median time since cancer diagnosis of 25 (12 – 41) years. Patients and controls were recruited from the South Medical Region of Sweden.

Methods: The study included 167 female CCS, median age 34 (19 – 57) years, diagnosed with childhood cancer at median age 8.4 (0.1 – 17.9) years together with 164 controls, matched for age, sex, ethnicity, residence, and smoking habits. All subjects were examined with fasting glucose, insulin, HbA1c, and lipid profile. Fat mass was calculated with dual-energy X-ray absorptiometry (DXA), questionnaires for medication were obtained. Detailed information of cancer treatment was available.

Results: POI was present in 13% (22/167) among CCS (hypothalamic/pituitary cause excluded) and in none among controls. MetS was present in 14% (24/167) among all CCS (p = 0.001), in 23% (5/22) of those with POI (p < 0.001), compared with 4% (6/164) among controls. OR for MetS in all CCS compared with controls was 4.4 (95% CI 1.8, 11.1) (p = 0.002) and among CCS with POI the OR was 7.7 (CI 2.1, 28.1) (p = 0.002).

Conclusion: The prevalence of MetS was higher in females treated for childhood cancer compared with controls and the presence of POI significantly increased the risk of developing MetS.

Free access

Ilpo T Huhtaniemi, Abdelouahid Tajar, David M Lee, Terence W O'Neill, Joseph D Finn, György Bartfai, Steven Boonen, Felipe F Casanueva, Aleksander Giwercman, Thang S Han, Krzysztof Kula, Fernand Labrie, Michael E J Lean, Neil Pendleton, Margus Punab, Alan J Silman, Dirk Vanderschueren, Gianni Forti, Frederick C W Wu, and the EMAS Group

Background

The limitations of serum testosterone and estradiol (E2) 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 E2 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 E2 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 E2 measurements (R=0.32, P<0.001, at E2 <40.8 pmol/l, and R=0.74, P<0.001, at E2 >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 E2 (<40.7 pmol/l) were 13.3 and 99.3%, and for high E2 (>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 E2 measurements showed poor correlation with MS and may only be suitable for the detection of high E2 in men.

Free access

David M Lee, Martin K Rutter, Terence W O'Neill, Steven Boonen, Dirk Vanderschueren, Roger Bouillon, Gyorgy Bartfai, Felipe F Casanueva, Joseph D Finn, Gianni Forti, Aleksander Giwercman, Thang S Han, Ilpo T Huhtaniemi, Krzysztof Kula, Michael E J Lean, Neil Pendleton, Margus Punab, Alan J Silman, Frederick C W Wu, and the European Male Ageing Study Group

Objectives

Low serum 25-hydroxyvitamin D (25(OH)D) and elevated parathyroid hormone (PTH) levels have been linked to insulin resistance, the metabolic syndrome (MetS) and its components. Data in healthy, community-dwelling Europeans are lacking, and previous studies have not excluded subjects receiving drug treatments that may distort the relationship between 25(OH)D/PTH and MetS. The aim of our analysis was to examine the association of 25(OH)D and PTH with Adult Treatment Panel III-defined MetS in middle-aged and older European men.

Design

This was a population-based, cross-sectional study of 3369 men aged 40–79 years enrolled in the European Male Ageing Study.

Results

After exclusion of subjects with missing data, 3069 men with a mean (±s.d.) age of 60±11 years were included in the analysis. Age-adjusted 25(OH)D levels were inversely associated with waist circumference, systolic blood pressure (BP), triglycerides, and glucose (all P<0.01). Age-adjusted PTH levels were only associated with waist and diastolic BP (both P<0.05). After adjusting for age, centre, season and lifestyle factors the odds for MetS decreased across increasing 25(OH)D quintiles (odds ratios 0.48 (95% confidence intervals 0.36–0.64) highest versus lowest quintile; P trend<0.001). This relationship was unchanged after adjustment for PTH, but was attenuated after additional adjustment for homoeostasis model assessment of insulin resistance (0.60 (0.47–0.78); P trend<0.001). There was no association between PTH and MetS.

Conclusions

Our results demonstrate an inverse relationship between 25(OH)D levels and MetS, which is independent of several confounders and PTH. The relationship is partly explained by insulin resistance. The clinical significance of these observations warrants further study.

Free access

Robert J A H Eendebak, Ilpo T Huhtaniemi, Stephen R Pye, Tomas Ahern, Terence W O’Neill, György Bartfai, Felipe F Casanueva, Mario Maggi, Gianni Forti, Robert D Alston, Aleksander Giwercman, Thang S Han, Krzysztof Kula, Michael E J Lean, Margus Punab, Neil Pendleton, Brian G Keevil, Dirk Vanderschueren, Martin K Rutter, Gindo Tampubolon, Royston Goodacre, Frederick C W Wu, and for the EMAS Group

Context

The androgen receptor (AR) gene exon 1 CAG repeat length has been proposed to be a determinant of between-individual variations in androgen action in target tissues, which might regulate phenotypic differences of human ageing. However, findings on its phenotypic effects are inconclusive.

Objective

To assess whether the AR CAG repeat length is associated with longitudinal changes in endpoints that are influenced by testosterone (T) levels in middle-aged and elderly European men.

Design

Multinational European observational prospective cohort study.

Participants

A total of 1887 men (mean ± s.d. age: 63 ± 11 years; median follow up: 4.3 years) from centres of eight European countries comprised the analysis sample after exclusion of those with diagnosed diseases of the hypothalamic–pituitary–testicular (HPT) axis.

Main outcome measures

Longitudinal associations between the AR CAG repeat and changes in androgen-sensitive endpoints (ASEs) and medical conditions were assessed using regression analysis adjusting for age and centre. The AR CAG repeat length was treated as both a continuous and a categorical (6–20; 21–23; 24–39 repeats) predictor. Additional analysis investigated whether results were independent of baseline T or oestradiol (E2) levels.

Results

The AR CAG repeat, when used as a continuous or a categorical predictor, was not associated with longitudinal changes in ASEs or medical conditions after adjustments. These results were independent of T and E2 levels.

Conclusion

Within a 4-year time frame, variations in the AR CAG repeat do not contribute to the rate of phenotypic ageing, over and above, which might be associated with the age-related decline in T levels.

Free access

Thang S Han, Abdelouahid Tajar, Terence W O'Neill, Min Jiang, György Bartfai, Steven Boonen, Felipe Casanueva, Joseph D Finn, Gianni Forti, Aleksander Giwercman, Ilpo T Huhtaniemi, Krzysztof Kula, Neil Pendleton, Margus Punab, Alan J Silman, Dirk Vanderschueren, Michael E J Lean, Frederick C W Wu, and the EMAS group

Background

Few published data link overweight and obesity with measures of quality of life (QoL) including sexual health in men.

Objective

To assess the association of overweight/obesity with impairment of physical and psychological QoL and sexual functions in men.

Design and setting

Cross-sectional, multicentre survey of 3369 community-dwelling men aged 40–79 (mean±s.d., 60±11) years randomly selected from eight European centres.

Outcomes

Adiposity was assessed by body mass index (BMI) and waist circumference (WC), QoL and functional impairments by physical and psychological function domains of the Short Form-36 questionnaire, Beck's Depression Inventory and the European Male Ageing Study sexual function questionnaire.

Results

Complete data on sexual activities and erectile function were available in 2734 (92%) and 3193 (95%) of the participants respectively. From the population studied, 814 men were obese (BMI ≥30 kg/m2) and 1171 had WC ≥102 cm, 25% of all men were unable to do vigorous activity and 2–13% reported depressive symptoms. Symptoms of sexual dysfunction ranged between 22% (low sexual desire) and 40% (infrequent morning erections) of the participants. Among obese men with both BMI ≥30 kg/m2 and WC ≥102 cm, at least one symptom of impaired physical, psychological and sexual function was reported by 41, 43 and 73% of the participants respectively. Compared with the reference group of non-obese men (BMI <30 kg/m2 and WC <102 cm), men with BMI ≥30 kg/m2 and WC ≥102 cm more frequently reported at least one symptom of impaired physical function (odds ratio (OR)=2.67; confidence interval (CI): 2.07–3.45, P<0.001), impaired psychological function (OR=1.48; CI: 1.14–1.90, P<0.01) and impaired sexual function (OR=1.45; CI: 1.14–1.85, P<0.01). These functional impairments were also more prevalent in men who had WC ≥102 cm even with BMI <30 kg/m2, but those with BMI ≥30 kg/m2 and WC <102 cm generally did not suffer from increased impaired physical or sexual health. Men with high BMI and WC were at even greater likelihood of having a composite of two or more or three or more symptoms compared with those with normal BMI and WC.

Conclusions

Men with high WC, including those who are ‘non-obese’ with BMI <30 kg/m2, have poor QoL with symptoms of impaired physical, psychological and sexual functions. Health promotion to improve QoL should focus on prevention of obesity and central fat accumulation.

Free access

David M Lee, Abdelouahid Tajar, Stephen R Pye, Steven Boonen, Dirk Vanderschueren, Roger Bouillon, Terence W O'Neill, Gyorgy Bartfai, Felipe F Casanueva, Joseph D Finn, Gianni Forti, Aleksander Giwercman, Thang S Han, Ilpo T Huhtaniemi, Krzysztof Kula, Michael E J Lean, Neil Pendleton, Margus Punab, Frederick C W Wu, and the EMAS study group

Objective

Interrelationships between hormones of the hypothalamic–pituitary–testicular (HPT) axis, hypogonadism, vitamin D and seasonality remain poorly defined. We investigated whether HPT axis hormones and hypogonadism are associated with serum levels of 25-hydroxyvitamin D (25(OH)D) in men.

Design and methods

Cross-sectional survey of 3369 community-dwelling men aged 40–79 years in eight European centres. Testosterone (T), oestradiol (E2) and dihydrotestosterone were measured by gas chromatography–mass spectrometry; LH, FSH, sex hormone binding globulin (SHBG), 25(OH)D and parathyroid hormone by immunoassay. Free T was calculated from total T, SHBG and albumin. Gonadal status was categorised as eugonadal (normal T/LH), secondary (low T, low/normal LH), primary (low T, elevated LH) and compensated (normal T, elevated LH) hypogonadism. Associations of HPT axis hormones with 25(OH)D were examined using linear regression and hypogonadism with vitamin D using multinomial logistic regression.

Results

In univariate analyses, free T levels were lower (P=0.02) and E2 and LH levels were higher (P<0.05) in men with vitamin D deficiency (25(OH)D <50 nmol/l). 25(OH)D was positively associated with total and free T and negatively with E2 and LH in age- and centre-adjusted linear regressions. After adjusting for health and lifestyle factors, no significant associations were observed between 25(OH)D and individual hormones of the HPT axis. However, vitamin D deficiency was significantly associated with compensated (relative risk ratio (RRR)=1.52, P=0.03) and secondary hypogonadism (RRR=1.16, P=0.05). Seasonal variation was only observed for 25(OH)D (P<0.001).

Conclusions

Secondary and compensated hypogonadism were associated with vitamin D deficiency and the clinical significance of this relationship warrants further investigation.

Free access

David M Lee, Aslan Ulubaev, Abdelouahid Tajar, Stephen R Pye, Neil Pendleton, Nitin Purandare, Terence W O'Neill, Daryl B O'Connor, Fernand Labrie, Hazel Platt, Debbie Payne, Gyorgy Bartfai, Steven Boonen, Felipe F Casanueva, Joseph D Finn, Gianni Forti, Aleksander Giwercman, Thang S Han, Ilpo T Huhtaniemi, Krzysztof Kula, Michael E J Lean, Margus Punab, Alan J Silman, Dirk Vanderschueren, Frederick C W Wu, and the EMAS study group

Objective

Data remain divergent regarding the activational effects of endogenous hormones on adult cognitive function. We examined the association between cognition, hormones and androgen receptor (AR) CAG repeat length in a large cohort of men.

Design

Community-based, cross-sectional study of 3369 men aged 40–79 years.

Methods

Cognition tests were the Rey-Osterrieth Complex Figure, Camden Topographical Recognition Memory and Digit-Symbol Substitution. A fluid cognition (FC) z-score was computed from the individual tests. Testosterone, oestradiol (OE2) and 5α-dihydrotestosterone were measured by gas chromatography–mass spectrometry; DHEAS, LH, FSH and sex hormone-binding globulin (SHBG) by electrochemiluminescence. Free testosterone and OE2 were calculated from total hormone, SHBG and albumin. CAG repeat lengths were assayed by PCR genotyping.

Results

Total testosterone and free testosterone were associated with higher FC z-scores, LH and FSH with lower FC z-scores in age-adjusted linear regressions. After adjusting for health, lifestyle and centre, a modest association was only observed between DHEAS and a lower FC z-score (β=−0.011, P=0.02), although this was driven by subjects with DHEAS levels >10 μmol/l. Locally weighted plots revealed no threshold effects between hormones and FC. There was no association between CAG repeat length and FC z-score after adjustment for age and centre (β=−0.007, P=0.06), nor any interaction effect between CAG repeat length and hormones.

Conclusion

Our results suggest that endogenous hormones are not associated with a vision-based measure of FC among healthy, community-dwelling men. Further studies are warranted to determine whether ‘high’ DHEAS levels are associated with poorer performance on a broader range of neuropsychological tests.

Free access

Steven Boonen, Stephen R Pye, Terence W O'Neill, Pawel Szulc, Evelien Gielen, Herman Borghs, Sabine Verschueren, Frank Claessens, Judith E Adams, Kate A Ward, Gyorgy Bartfai, Felipe Casanueva, Joseph D Finn, Gianni Forti, Aleksander Giwercman, Thang S Han, Ilpo T Huhtaniemi, Krzysztof Kula, Fernand Labrie, Michael E J Lean, Neil Pendleton, Margus Punab, Alan J Silman, Abdelouahid Tajar, Frederick C W Wu, Dirk Vanderschueren, and the EMAS Group

Objective

To assess the influence of sex hormones on markers of bone turnover and to explore the association between these markers and bone health in middle-aged and elderly European men.

Design

A cross-sectional population-based survey.

Methods

Men aged 40–79 years were recruited from population registers in eight European centres. Subjects completed a postal questionnaire which included questions concerning lifestyle and were invited to undergo quantitative ultrasound (QUS) of the calcaneus and to provide a fasting blood sample from which the bone markers serum N-terminal propeptide of type 1 procollagen (P1NP) and crosslinks (β C-terminal cross-linked telopeptide (β-cTX)), total testosterone, total oestradiol (E2), sex hormone-binding globulin (SHBG) and insulin-like growth factor 1 (IGF1) were measured. Dual-energy X-ray absorptiometry (DXA) of the hip and lumbar spine was performed in two centres.

Results

A total of 3120, mean age 59.9 years (s.d.=11.0) were included. After adjustment for centre, age, height, weight, lifestyle factors, season and other hormones, total and free E2 were negatively associated with β-cTX but not P1NP while SHBG, IGF1 and parathyroid hormone (PTH) were positively associated with both β-cTX and P1NP. Total or free testosterone was not independently associated with either bone marker. After the same adjustments, higher levels of both bone markers were significantly associated with lower QUS parameters and lower DXA-assessed bone density at the total hip and lumbar spine.

Conclusions

E2, SHBG, IGF1 and PTH contribute significantly to the regulation/rate of bone turnover in middle-aged and older European men. Higher rates of bone remodelling are negatively associated with male bone health.