Development of and Recovery from Secondary Hypogonadism in Ageing Men: Prospective Results

1 2 1Development of and Recovery from Secondary Hypogonadism in Ageing Men: Prospective Results 2from the EMAS3Giulia Rastrelli1, Emma L. Carter2, Tomas Ahern2, Joseph D. Finn2, Leen Antonio3, Terence W. O’Neill4, 4Gyorgy Bartfai5, Felipe F. Casanueva6, Gianni Forti1, Brian Keevil7, Mario Maggi1, Aleksander Giwercman8, 5Thang S. Han9, Ilpo T Huhtaniemi10, Krzysztof Kula11, Michael E. J. Lean12, Neil Pendleton13, Margus 6Punab14, Dirk Vanderschueren3, Frederick C. W. Wu2 and the EMAS study group.71Sexual Medicine and Andrology Unit, Department of Experimental Clinical and Biomedical Sciences, 8University of Florence, Florence, Italy; 2Andrology Research Unit, Centre for Endocrinology & Diabetes, 9Institute of Human Development, Old St Mary’s Building, The University of Manchester, Manchester, UK; 103Department of Andrology and Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium, 4Arthritis 11Research UK Centre for Epidemiology, Institute of Inflammation and Repair, Faculty of Medical and Human 12Sciences, Manchester Academic Health Science Centre, University of Manchester and NIHR Manchester 13Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Manchester, UK; 145Department of Obstetrics, Gynaecology and Andrology, Albert Szent-György Medical University, Szeged, 15Hungary; 6Department of Medicine, Santiago de Compostela University, Complejo Hospitalario 16Universitario de Santiago (CHUS); CIBER de Fisiopatología Obesidad y Nutricion (CB06/03), Instituto 17Salud Carlos III; Santiago de Compostela, Spain; 7Department of Clinical Biochemistry, University Hospital 18of South Manchester, Manchester, UK, 8Reproductive Medicine Centre, Malmö University Hospital, 19University of Lund, Sweden; 9Department of Endocrinology, Ashford and St Peter’s National Health Service 20Trust, Surrey, UK; 10Department of Surgery and Cancer, Institute of Reproductive and Developmental 21Biology, Imperial College London, Hammersmith Campus, London, UK; 11Department of Andrology and 22Reproductive Endocrinology, Medical University of Łódź, Łódź, Poland; 12Department of Human Nutrition, 23University of Glasgow, Glasgow, UK; 13School of Community Based Medicine, The University of 24Manchester, Hope Hospital, Salford, UK; 14Andrology Unit, United Laboratories of Tartu University Clinics, 25Tartu, Estonia. 2627Abbreviated title: Secondary Hypogonadism: Development and Recovery2829Key terms: hypogonadotropic hypogonadism, testosterone, androgen deficiency, obesity, co-morbidity 3031Word count: 347232Number of figures and tables: 6333 1 4 5 6 34Corresponding Author and person to whom reprint request should be addressed:35Giulia Rastrelli, MD, PhD36Department of Experimental Clinical and Biomedical Sciences37University of Florence38Viale Pieraccini,6, 50139, Florence, Italy39Phone: +39 333496919040Fax: +39 055427137141e-mail: [email protected]4243Grants and fellowships supporting the writing of the paper: The European Male Aging Study is funded44by the Commission of the European Communities Fifth Framework Program “Quality of Life and45Management of Living Resources” Grant QLK6-CT-2001-00258 and facilitated by the Manchester46Biomedical Research Centre and the NIHR Greater Manchester: Clinical Research Network. Additional47support was also provided by Arthritis Research UK and the National Institute for Health Research and the48Manchester Biomedical Research Centre.4950Disclosure statement: GR, ELC, TA, JDF, LA, TWO, GB, FFC, GF, BK, MM, AG, TSH, KK, MEJL, NP,51MP, DV have nothing to declare. ITH has research contracts with Ferring Pharmaceuticals and Pantarhei52Bioscience. ITH consults for Novartis. FCWW has consulted for Bayer-Schering, Eli Lilly, Repros53Therapeutics Inc. and Besins Healthcare and also participated in advisory board meetings and54lectured on their behalf. FCWW has received grant support (2010-2014) from Bayer Schering AG,55PAREXEL International and Besins Healthcare.56575859607 2 8 9 10 61Abstract 62Context: Secondary hypogonadism is common in ageing men; its natural history and predisposing factors63are unclear.64Objectives: 1)To identify factors which predispose eugonadal men (T ≥10.5nmol/L) to develop biochemical65secondary hypogonadism (T<10.5nmol/L, LH≤9.4U/L) and secondary hypogonadal men to recover to66eugonadism. 2)To characterize clinical features associated with these transitions.67Design: Prospective observational general population cohort survey.68Setting: Clinical research centres.69Participants: 3369 community-dwelling men aged 40-79 yr in eight European centres.70Intervention: Observational follow-up of 4.3 years.71Main Outcome Measure: Subjects were categorised according to change/no change in biochemical gonadal72status during follow-up into persistent eugonadal (n=1909), incident secondary hypogonadal (n=140),73persistent secondary hypogonadal (n=123) and recovered from secondary hypogonadism to eugonadism74(n=96). Predictors and changes in clinical features associated with incident secondary hypogonadism and75recovery from secondary hypogonadism were analysed by regression models.76Results: The incidence of secondary hypogonadism was 155.9/10,000/year, while 43.8% of men with77secondary hypogonadism recovered to eugonadism. Incident secondary hypogonadism was predicted by78obesity [BMI≥30kg/m2: odds ratio (OR)=2.86(95% confidence interval 1.67;4.90);p<0.0001],weight gain79[OR=1.79(1.15;2.80);p=0.011] and increased waist circumference [OR=1.73(1.07;2.81);p=0.02680and 2.64(1.66;4.21);p<0.0001, for waist circumference 94-102 and ≥102 cm, respectively]. Incident81secondary hypogonadal men experienced new/worsening sexual symptoms [low libido, erectile dysfunction82and infrequent spontaneous erections]. Recovery from secondary hypogonadism was predicted by non-83obesity [OR=2.28(1.21;4.31);p=0.011], weight loss [OR=2.24(1.04;4.85);p=0.042], normal waist84circumference [OR=1.93(1.01;3.70)p=0.048], younger age [<60yr OR=2.32(1.12;4.82);p=0.024] and higher85education [OR=2.11(1.05;4.26);p=0.037], but symptoms did not show significant improvement.86Conclusion: Obesity-related metabolic and lifestyle factors predispose older men to develop secondary87hypogonadism, which is frequently reversible with weight loss. 8811 3 12 13 14 89Introduction90After the third decade T decreases in men by 0.4-2% per year (1). Besides ageing, other risk factors91contribute substantially to the T decline, particularly and irrespective of age, obesity (1,2). There is also92evidence suggesting that low T can promote fat accumulation (3) suggesting a bi-directional relationship93between obesity and low T. Longitudinal data from the European Male Ageing Study (EMAS) showed that94weight gain was progressively associated with a decline in T levels without a concomitant change in LH (4),95compatible with secondary hypogonadism (sHG). Furthermore, weight loss was proportionately associated96with increases in T (4), suggesting that sHG is potentially reversible. 97sHG accounts for more than 50% of men with low T in the general population (5) and in patients with sexual98dysfunction (6). To better understand the natural history and clinical significance of sHG, it is important to99further investigate longitudinally the role of obesity, relative to other potential risk factors, in predicting the100development of and recovery from sHG.101Symptoms of androgen deficiency in the presence of low T provide the diagnostic cornerstone of the102syndrome of hypogonadism (7). Late-onset hypogonadism (LOH) has been stringently defined by us as103subnormal T associated with three sexual symptoms (5,8). However, the cross-sectional association between104low T and symptoms was attenuated after adjusting for body mass index (BMI) and comorbidities (5),105underlining the multi-causal origin of putative symptoms of hypogonadism in ageing men. Moreover,106obesity, independent of T, is associated with sexual (9) and psychological symptoms (10) as well as impaired107physical activity (11). Confirming the appearance of these symptoms with the development of biochemical108hypogonadism and/or their resolution following recovery to eugonadism (EUG) would support their109relevance as specific clinical markers of androgen deficiency, important in the diagnostic workup of men110with low T.111112The aim of the study was to identify predictors of, and symptoms associated with incident sHG (isHG) and113recovery from sHG (rsHG) in middle-aged and older men from the general population.114115Materials and methods116Participants and study design15 4 16 17 18 117The EMAS design and methods have been previously described (12,13). Briefly, an age-stratified sample of1183,369 men aged 40–79 (mean±SD:60±11) years were recruited from population registers in eight European119centres: Manchester (UK), Leuven (Belgium), Malmö (Sweden), Tartu (Estonia), Lodz (Poland), Szeged120(Hungary), Florence (Italy) and Santiago de Compostela (Spain). Participants attended research clinics at121baseline and 4.3 years later (range 3.0–5.7 years) for follow-up assessments (12,13). During this period, 193122men died, 334 were lost to follow-up and 106 were institutionalised or became too frail. Ethical approval for123the study was obtained according to institutional requirements in each centre. All participants provided124written, informed consent. They completed questionnaires at both baseline and follow-up (12,13) about125smoking, alcohol consumption and currently treated comorbidities (1). Anthropometric measurements,126Reuben’s physical performance test (PPT) and psychomotor processing speed (Digit Symbol Substitution127Test (DSST)) were performed according to standardised methods (12,13). Physical, sexual and psychological128symptoms were determined from responses to the MOS 36-item Short-Form health survey (SF36), the129EMAS Sexual Function Questionnaire and the Beck Depression Inventory (BDI), respectively.130Hormone measurements131Single, fasting morning (before 10:00 h) venous blood samples were obtained at baseline and follow-up. T132was measured by liquid chromatography–tandem mass spectrometry (LC–MS/MS), with paired baseline and133follow-up samples analysed simultaneously. LH, FSH and SHBG were measured by the E170 platform134electrochemiluminescence immunoassay (Roche Diagnostics). Free T was calculated using the Vermeulen135formula (14). Intra- and inter-assay coefficients of variation (CV) were: T 4.0 and 5.6%; SHBG 1.7 and1363.2%, LH 1.9 and 3.0% and FSH 1.8 and 5.3%, respectively. The lower limit of total T measurement was1370.17 nmol/l (0.05 ng/ml). Insulin was assayed using chemiluminescence (CVs: 3.9% and 5%). Biochemistry138and haematology parameters were performed with standardized measurements, undertaken in hospital139laboratories in each centre. Insulin resistance was calculated using the homoeostasis model assessment of140insulin resistance [HOMA-IR=fasting insulin (U/ml)×fasting glucose (mmol/l)/22.5] (15).141Gonadal status142Participants with T≥10.5 nmol/l were defined as EUG, and sHG when T<10.5 nmol/l and LH<9.4 U/L (5).143Subjects were further categorised by their change in gonadal status into (a) persistent EUG (pEUG) – EUG19 5 20 21 22 144at baseline and follow-up, (b) incident sHG (isHG) – EUG at baseline and sHG at follow-up, (c) persistent145sHG (psHG) – sHG at baseline and follow-up, and (d) rsHG – sHG at baseline and EUG at follow-up. 146Statistical analysis147Baseline differences between isHG and pEUG and between rsHG and psHG in hormone levels,148anthropometrics, biochemistry, symptoms, health and lifestyle measures were initially evaluated by149Student’s t-test for continuous variables and Χ2 test for categorical variables. 150Multiple regression models, adjusted for centre as a random-effect, were used to account for the hierarchical151study design (individuals nested within centre). The relationships between gonadal status and putative152predictors were assessed using multilevel binary logistic regression models, where gonadal status was the153outcome, with the pEUG or psHG group being the referent for the analyses of predictors of isHG or rsHG,154respectively. Nine factors were included as fixed-effect predictors: age, smoking status (current smoker -155yes/no), alcohol intake (alcohol consumption for ≥5 days per week vs. less), education level [low156(compulsory education only), medium (non-compulsory education below university level) or high (university157education)], Physical Activity Scale for the Elderly ((PASE) score ≤78 vs. >78), Chronic widespread pain158(yes/no), marital status (no partner, having a partner but not living together or having a partner and living159together), comorbidity (presence/absence of at least one self-reported disorder), BMI (<25 kg/m 2, 25–29.9160kg/m2, and ≥30 kg/m2) and waist circumference (WC) (<94 cm, 94-101.9 cm, and ≥102 cm).161The relationship between gonadal status and clinical features of HG was investigated using binary logistic162regression models with symptoms, dichotomized as stable or new/worsened, as the outcome, when assessing163outcomes of isHG, and as stable or resolved/improved, when assessing outcomes of rsHG. A symptom was164defined as new when absent at baseline and present at follow-up and worsened when present at baseline but165with a lower severity grading than at follow-up. A symptom was defined as resolved when present at166baseline and absent at follow-up and improved when present at follow-up with a lower severity grading than167at baseline. 168Differences in clinical characteristics between isHG and pEUG or rsHG and psHG at baseline and changes169over time were investigated by multiple logistic regression models adjusted for age (as a continuous170variable), centre, baseline BMI (as a continuous variable), presence of at least one comorbidity at baseline,171smoking, and alcohol intake. 23 6 24 25 26 172Linear regression models were used to evaluate the association between isHG or rsHG and baseline levels or173percentage change of metabolic and hematologic parameters, expressed as continuous variables.174For isHG predictor analysis, weight gain was defined as ≥5% increase of the baseline value. In the rsHG175predictor analysis, weight loss was defined as ≥5% decrease of the baseline value.176Results from logistic regression models are presented as odds ratios (OR) and 95% confidence interval (CI)177and from linear regression models as β coefficients with 95% CI. All statistical analyses were conducted178using SPSS for Windows 20.1 (IBM, Armonk, NY, USA).179180Results181Natural history of secondary hypogonadism (sHG)182Of the 3,369 men that participated in EMAS (Figure 1): 193 were excluded at baseline because of medical183conditions (known pituitary-testicular diseases and medications affecting T); 165 died during the follow-up184period; 93 were institutionalised or too frail to attend for follow-up and 314 were lost to follow-up for other185reasons. Another 162 were excluded at follow-up because of medical conditions/medications, and 121 were186excluded due to missing total T and/or LH levels at baseline and/or follow-up. Among the baseline attendees,187the prevalence of sHG was 10.0% (n=318). In this sHG group, mortality and lost to follow-up rates were 8.2188and 11.3%, compared to the entire cohort’s rates of 5.2% and 9.9%, respectively. In the analytical sample of1892,268 men, 1,909 were pEUG, 140 isHG, 123 psHG and 96 rsHG (Figure 1). The prevalence of sHG at190follow-up was 11.0% and the incidence of sHG from EUG was 6.28% in 4.3 years or 155.9 per 10,000 per191year or 1.6% per annum. The recovery rate from sHG to EUG was 30.2% (96/318) or 42.9% (96/224192excluding 94 subjects not attending the second assessment) in 4.3 years.193Compared with the analytical sample, men who died, were institutionalized or were too frail to attend were194older, had lower free T, higher SHBG and gonadotropins, but not significantly different total T levels and195reported more diabetes mellitus, cardiovascular diseases and worse physical performance (Supplementary196table 1). Conversely, subjects who were lost to follow-up for other reasons were similar to the analytical197group, except for a higher prevalence of smoking and metabolic syndrome (MetS) and lower psychomotor198processing speed.199 Characteristics of iSHG27 7 28 29 30 200Lower mean total T, free T, SHBG, LH and FSH levels were already apparent in iSHG men compared to201pEUG, at baseline; these differences were replicated and amplified at follow-up (Table 1). isHG men were202overweight/obese at baseline, with higher prevalence of comorbidities and MetS; these factors increased203further at follow-up. isHG men also showed differences in baseline and follow-up metabolic profiles with204lower high density lipoprotein (HDL), higher triglycerides, glucose and HOMA-IR. 205Multiple logistic regression modelling identified obesity [OR=2.86 (1.67; 4.90),p<0.0001], as an206independent predictor of isHG (Figure 2A). Substituting WC for BMI categories showed that increased WC207was a predictor of isHG [OR=1.73(1.07;2.81);p=0.026 and 2.64(1.66;4.21);p<0.0001for WC 94-102 cm and208WC>102 cm respectively] and that older men (≥70yr) demonstrated a significantly lower predisposition to209develop sHG compared to younger subjects [OR=0.51(0.28;0.96),p=0.035] (Figure 2C). Weight gain of ≥5%210was also a risk factor for isHG [OR=1.79(1.15; 2.80),p=0.011]. No significant interaction effect was found211between the variables in the model.212Prevalence of symptoms at baseline and follow-up, as well as new/worsening symptoms during follow-up213are shown in Table 1. Men with isHG, compared with pEUG, did not show any difference in prevalence of214symptoms at baseline before or after adjustment (Table 2, Figure 3A). isHG was associated with a higher215prevalence of decreased libido at follow-up and, although just missing statistical significance, the prevalence216of erectile dysfunction (ED) and infrequent morning erections were higher than pEUG at follow-up (Table 2217and Figure 3B). isHG, however, was significantly associated with the development or worsening of all three218sexual symptoms and one physical symptom (impaired vigorous activity) (Table 2). Incremental adjustments219for potential confounders (Table 2) showed that isHG maintained its association only with new/worsening220sexual symptoms (Figure 3C).221Compared with pEUG, isHG subjects had significantly higher total cholesterol at baseline (Table 3). In222addition, isHG was associated with a significant increase in HDL-cholesterol (Table 3). The apparent223relationship between isHG with increased HDL-cholesterol became insignificant (β=0.44 [-0.08;2240.95],p=0.096) after adjusting for those starting lipid-lowering medications during follow-up. iSHG men did225not differ from pEUG at baseline, but they showed a significant decrease in feeling of physical well-being226(SF36-physical component score), and deterioration in PPT rating (Table 3).22731 8 32 33 34 228Characteristics of rsHG229At baseline, rsHG subjects had higher SHBG and total T levels as compared with psHG (Table 1). rsHG men230had a more favourable baseline metabolic profile, with lower triglycerides and a lower prevalence of MetS231than psHG. They also showed lower weight, BMI and WC. rsHG was independently predicted by being232younger and non-obese BMI [OR=2.32(1.12;4.82);p=0.024 and OR=2.28(1.21;4.31);p=0.011; respectively]233(Figure 2B). Normal WC was a significant predictor for rsHG [OR=1.93(1.01;3.70) p=0.048] (Figure 2D). A234higher level of education predicted rsHG [OR=2.11 (1.05;4.26);p=0.037] (Figure 2B and 2D). Weight235reduction (≥5%) during follow-up, when substituted for BMI, was also a predictor for rsHG236[OR=2.24(1.04;4.85);p=0.042]. No interaction effect was found between the variables in the model.237Prevalences of symptoms at baseline and follow-up as well as recovery/improvement of symptoms during238follow-up in psHG and rsHG are shown in Table 1. No significant association was found between rsHG with239either baseline or follow-up prevalence or recovery/improvement of sexual, physical or psychological240symptoms (Figure 3D). rsHG, compared with psHG, had significantly lower total cholesterol and241triglycerides at baseline and a significant decrease in insulin during follow-up (Table 3), whereas no242significant difference was found for physical and psychological function. 243244Discussion245The longitudinal data in this observational cohort of older men from the general population highlight the role246of obesity and weight gain as the most important predictors for developing sHG, showing for the first time247that isHG is associated with appearance or worsening of sexual symptoms only. Another new finding is that248sHG is potentially reversible in a substantial proportion of men and that recovery is predicted by non-obesity,249weight loss, younger age and higher education.250Predictors of isHG251As previously shown by cross-sectional data from EMAS, BMI is an important correlate of sHG (5). In this252longitudinal evaluation, we are able to confirm that BMI predicts isHG. Our finding of obesity as a253determinant for T decline, independent of LH, confirms earlier longitudinal results (16,17). The association254between obesity and HG is complex and poorly understood. Obesity can induce peripheral and central255insulin resistance (18), pro-inflammatory cytokine production (TNFα and IL-6) from adipocytes (19) and35 9 36 37 38 256central nervous system endocannabinoid release (20) that can induce down-regulation of hypothalamic257function. In addition, adipocytokines such as leptin and adiponectin have been shown to modulate GnRH and258gonadotropin secretion (21) and to influence testicular T production (22). Conversely, the suggested role for259an excess of estrogens, due to an increased aromatase activity in obese subjects, in reducing the GnRH-260gonadotropin secretion has not been confirmed in obese diabetic (23) and non-diabetic men (5), their261estradiol levels being lower, rather than higher and correlated with T levels but not with BMI. 262Our results also demonstrated a lower probability that older men will develop sHG. Cross-sectional data263from EMAS have shown that ageing is associated with elevated gonadotropins and primary HG (1,5).264Disorders causing a derangement of hypothalamic-pituitary axis superimposed on a background of high265gonadotropin (as in older men) are less likely to suppress LH to values below the threshold used to define266sHG. Men attending both phases of the study are healthier as compared with those who did not (see267Supplementary table 1). It is therefore conceivable that among those attending for follow-up, a survival bias268may have selected healthier older men who are less prone to develop sHG (24).269270Developing sHG: clinical features271In this study, development of sHG was associated, independently of BMI, comorbidities and lifestyle, with272new or worsening sexual symptoms but not physical or psychological ones. This is consistent with our273previous cross-sectional analyses (8) indicating that these three sexual symptoms are the most specific274subjective features associated with low T. In addition to confirming the substantial baseline prevalence275(22.7-48.5%) of sexual symptoms, occurrence of new or worsening symptoms in the pEUG men is not276negligible (18%), albeit at a lower rate than in isHG men (25.6–28.1%), thus accounting for the weaker277association between isHG and increased prevalence of sexual symptoms at follow-up. This emphasises the278importance of the co-occurrence of all three sexual symptoms for increasing the probability of a robust279syndromic clustering with low T (8) which serves to provide the operational definition of symptomatic HG280or LOH. The longitudinal results, showing a specific association between the development of sHG with the281appearance or worsening of all three sexual symptoms prospectively, strongly endorse this approach. 282In the cross-sectional analyses, physical or psychological symptoms did not cluster together with low T, but,283one of the physical symptoms, decreased vigour, did show an inverse correlation with T levels (8).39 10 40 41 42 284Interestingly, in the longitudinal study, decreased vigorous activity is the only non-sexual symptom whose285new occurrence or worsening was significantly associated with isHG, until smoking and alcohol habits were286included as covariates. This emphasises the non-specific nature of non-sexual symptoms in sHG. However,287when considering the objective evaluation of physical performance and psychomotor processing speed (PPT288rating), a significantly greater reduction of these functions was found in isHG men, even though this was not289translated into a subjective perception of deterioration.290291Predictors of rsHG292The present results show that sHG is frequently (30.2%) reversible. Reversion to eugonadism was predicted293by lower BMI or WC, weight loss, younger age and higher education. The weight associations are294compatible with recent evidence from general population showing that weight loss is associated with a295proportionate increase in T levels (4,25). Thus, a >5% weight loss was associated with a significant increase296of T levels with the maximum effect in those men who lost ≥15% of weight when LH as well T increased297contemporaneously (4). Supervised dieting/exercise or bariatric surgery in obese men has been shown to298increase T and LH levels proportionally to the amount of weight loss (26). Interestingly, T increase attained299in treated subjects was higher in younger patients (26). We found, in addition to lower weight, that younger300age was an independent predictor of rsHG suggesting that the potential for weight loss to improve301hypothalamic-pituitary function may be eroded by adverse effects of ageing. A novel finding is that a higher302level of education was an independent predictor of rsHG. Education is a socio-economic status surrogate and303an important determinant of health inequality. Higher education is a protective factor for cardiovascular304diseases and all-cause mortality (27,28). Changes in behaviour in response to health education are most305beneficial in higher socio-economic groups (27-29) which may translate into improved metabolic status and306avoidance of obesity. Taken together, these results strongly suggest that sHG or functional hypothalamic307suppression associated with obesity, is potentially reversible with weight loss and amenable to lifestyle-308influenced metabolic modifications especially in younger educated men. Weight loss, especially in older309men, can be unintentional and due to comorbidities, cancer cachexia or other wasting diseases. However,310excluding men with incident cancer or heart diseases in our analyses did not influence the relationships311between BMI or weight loss with rsHG (data not shown), suggesting that the observed weight loss in those43 11 44 45 46 312obese middle-aged men (mean age 56 yr) with rsHG may well have been intentional and that the313concomitant rise in T is part of the overall, positive health outcome. 314315 Recovering from sHG: clinical features 316In this study, the anticipated association between rsHG and resolution/improvement of symptoms was not317found. There are a number of possible explanations. The relatively small sample size may not provide318sufficient statistical power to detect small differences between psHG (n=123) and rsHG (n=96), with a319minority only (2-11 men) showing symptomatic improvements. Both groups are subjected to uncontrolled320multiple and multi-directional influences during follow-up in this non-interventional observational study.321The increase in T documented at one time point at follow-up may not represent a sufficiently sustained322improvement to transmute into subjective symptomatic recovery. Randomized controlled trials of T323replacement therapy demonstrating improvements in sexual function (30), physical strength (31) and324depressive symptoms (32) usually show a 2-fold increase of T levels into the mid-normal physiological range325during treatment, for a minimum of 24 weeks. The spontaneous rise in T levels observed in our rsHG326subjects is relatively small by comparison (9.2 nmol/L at baseline increasing to 13.3 nmol/L at follow-up or a32745% increment) and may not be sufficient to drive improvements or resolution of sexual symptoms. Given328the high prevalence of sexual symptoms irrespective of the concentration of circulating T, a further329explanation could be that important non-hormonal (e.g. psychosocial and relational) factors contribute to the330persistence of symptoms, even after restoration of normal T levels .331332Strengths and limitations333The strengths of this study include a large unbiased sample from the general population, the prospective334design providing non-interventional longitudinal data to investigate the natural history and predictors of335hypogonadism and the standardised instruments applied across centres and between the phases of the study.336T levels were measured by LC–MS/MS with paired baseline and follow-up samples analysed337simultaneously. Limitations in EMAS have been described previously (13). The study interval of 4.3 years338may be relatively short for capturing the more subtle changes in signs and symptoms of HG in an339observational study. A single LH measurement only was available to categorise hypogonadism, but its co-47 12 48 49 50 340linearity with FSH would have minimised any potential misclassification. Also for T, a single measurement341only was available at each time point. However, T is a stable analyte (33) and single measurements of T on342morning samples, can provide representative and reliable data in large epidemiological studies such as the343EMAS.344345Conclusions346Our longitudinal data showed that overweight, obesity or weight gain predisposed older men to develop347sHG. Older men were at lower risk. Development of sHG was associated with the appearance of new or348worsening sexual, but not physical and psychological symptoms. sHG frequently remits spontaneously; this349is predicted by lower BMI or WC or weight loss, as well as younger age and higher education. Biochemical350reversal of sHG to EUG however was not accompanied by a significant symptomatic improvement. Further351studies are indicated to corroborate and extend the present results. 51 13 52 53 54 352ACKNOWLEDGEMENTS353The European Male Aging Study is funded by the Commission of the European Communities Fifth354Framework Program “Quality of Life and Management of Living Resources” Grant QLK6-CT-2001-00258355and facilitated by the Manchester Biomedical Research Centre and the NIHR Greater Manchester: Clinical356Research Network. Additional support was also provided by Arthritis Research UK and the National Institute357for Health Research and the Manchester Biomedical Research Centre. The Principal Investigator of EMAS is358Professor Frederick Wu, MD; Andrology Research Unit, University of Manchester, Manchester, UK. 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Study flow-chart showing exclusion of subjects and distribution of study sample by gonadal status476HG=hypogonadism; pEUG=persistent eugonadal at baseline; isHG=incident secondary hypogonadism;477psHG=persistent secondary hypogonadism; rsHG=recovery from secondary hypogonadism478479Figure 2480A. Predictors of incident secondary hypogonadism (sHG). Data are derived from multilevel binary regression481models, using centre as a random-effect covariate and age (categorized into 10 years age bands), smoking482status (current smoker – yes/no), alcohol intake (alcohol consumption for ≥5 per week vs. less), education483level [low (compulsory education only), medium (non-compulsory education below university level) or high484(university education)], Physical Activity Scale for the Elderly (PASE, score ≤78 and >78), Chronic485widespread pain (yes/no), marital status (no partner, having a partner not living together or having a partner486and living together), comorbidity (presence/absence of at least one self-reported disorder) and body mass487index (BMI) [<25 kg/m2, 25–29.9 kg/m2, and ≥30 kg/m2] as fixed-effect predictors. Gonadal status was the488outcome with the persistent eugonadal group being the referent category. The odd ratios are shown on a log-489scale.490B. Predictors of recovery from sHG. Data are derived from binary regression models, using centre as a491random-effect covariate and age [dichotomized into age <60 and age ≥60 years (yr)], smoking status (current492smokers – yes/no), alcohol intake (alcohol consumption for ≥5 per week vs. less), education level [low and493medium (completed non compulsory education but lower than university level) vs. high (university494education)], PASE (score ≤78 and >78), Chronic widespread pain (yes/no), marital status (no partner vs.495having a partner), BMI [<30 kg/m2 and ≥30 kg/m2], and comorbidity [presence/absence of at least one self-496reported disorder] as fixed-effect predictors. Gonadal status was the outcome with the persistent secondary497hypogonadal group being the referent category. The odd ratios are shown on a log-scale.498C. Predictors of incident sHG. Data are derived from multilevel binary regression models, using centre as a499random-effect covariate and age (categorized into 10 years age bands), smoking status (current smoker –500yes/no), alcohol intake (alcohol consumption for ≥5 per week vs. less), education level [low (compulsory501education only), medium (non-compulsory education below university level) or high (university education)],75 19 76 77 78 502Physical Activity Scale for the Elderly (PASE, score ≤78 and >78), Chronic widespread pain (yes/no),503marital status (no partner, having a partner not living together or having a partner and living together),504comorbidity (presence/absence of at least one self-reported disorder) and waist circumference (WC) [<94505cm, 94-102 cm, and ≥102 cm] as fixed-effect predictors. Gonadal status was the outcome with the persistent506eugonadal group being the referent category. The odd ratios are shown on a log-scale.507D. Predictors of recovery from sHG. Data are derived from binary regression models, using centre as a508random-effect covariate and age [dichotomized into age <60 and age ≥60 years (yr)], smoking status (current509smoker – yes/no), alcohol intake (alcohol consumption for ≥5 per week vs. less), education level [low and510medium (completed non compulsory education but lower than university level) vs. high (university511education)], PASE (score ≤78 and >78), Chronic widespread pain (yes/no), marital status (no partner vs.512having a partner), WC [<102 cm and ≥102 cm], and comorbidity [presence/absence of at least one self-513reported disorder] as fixed-effect predictors. Gonadal status was the outcome with the persistent secondary514hypogonadal group being the referent category. The odd ratios are shown on a log-scale.515* p<0.05; *** p<0.0001516517Figure 3. Upper panels: Association between incidence of secondary hypogonadism and baseline518prevalence (Panel A) or follow-up prevalence (Panel B) or incident/worsening (Panel C) of hypogonadism-519related symptoms [adjusted for age, centre, body mass index, comorbidities, smoking habits and alcohol520intake], using the group of persistent eugonadal subjects as referent category. The odd ratios are shown on a521log-scale. Lower panels: Association between recovery from secondary hypogonadism and baseline (Panel522D) or follow-up (Panel E) prevalence or recovery/improvement (Panel F) of hypogonadism-related523symptoms [adjusted for age, centre, body mass index, comorbidities, smoking habits and alcohol intake],524using the group of persistent secondary hypogonadal subjects as referent category. The odd ratios are shown525on a log-scale.526* p<0.05; ** p<0.0179 20 80

Development of and Recovery from Secondary Hypogonadism in Ageing Men: Prospective Results

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