1 2 1Development of and Recovery from Secondary Hypogonadism in Ageing Men: Prospective Results 2from the EMAS
3Giulia 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. 26
27Abbreviated title: Secondary Hypogonadism: Development and Recovery
28
29Key terms: hypogonadotropic hypogonadism, testosterone, androgen deficiency, obesity, co-morbidity
30
31Word count: 3472
32Number of figures and tables: 6
33
3 1 4 5 6 34Corresponding Author and person to whom reprint request should be addressed:
35Giulia Rastrelli, MD, PhD
36Department of Experimental Clinical and Biomedical Sciences
37University of Florence
38Viale Pieraccini,6, 50139, Florence, Italy
39Phone: +39 3334969190
40Fax: +39 0554271371
41e-mail: [email protected]
42
43Grants and fellowships supporting the writing of the paper: The European Male Aging Study is funded
44by the Commission of the European Communities Fifth Framework Program “Quality of Life and
45Management of Living Resources” Grant QLK6-CT-2001-00258 and facilitated by the Manchester
46Biomedical Research Centre and the NIHR Greater Manchester: Clinical Research Network. Additional
47support was also provided by Arthritis Research UK and the National Institute for Health Research and the
48Manchester Biomedical Research Centre.
49
50Disclosure 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 Pantarhei
52Bioscience. ITH consults for Novartis. FCWW has consulted for Bayer-Schering, Eli Lilly, Repros
53Therapeutics Inc. and Besins Healthcare and also participated in advisory board meetings and
54lectured on their behalf. FCWW has received grant support (2010-2014) from Bayer Schering AG,
55PAREXEL International and Besins Healthcare.
56
57
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7 2 8 9 10 61Abstract
62Context: Secondary hypogonadism is common in ageing men; its natural history and predisposing factors
63are unclear.
64Objectives: 1)To identify factors which predispose eugonadal men (T ≥10.5nmol/L) to develop biochemical
65secondary hypogonadism (T<10.5nmol/L, LH≤9.4U/L) and secondary hypogonadal men to recover to
66eugonadism. 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 gonadal
72status during follow-up into persistent eugonadal (n=1909), incident secondary hypogonadal (n=140),
73persistent secondary hypogonadal (n=123) and recovered from secondary hypogonadism to eugonadism
74(n=96). Predictors and changes in clinical features associated with incident secondary hypogonadism and
75recovery 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 with
77secondary hypogonadism recovered to eugonadism. Incident secondary hypogonadism was predicted by
78obesity [BMI≥30kg/m2: odds ratio (OR)=2.86(95% confidence interval 1.67;4.90);p<0.0001],weight gain
79[OR=1.79(1.15;2.80);p=0.011] and increased waist circumference [OR=1.73(1.07;2.81);p=0.026
80and 2.64(1.66;4.21);p<0.0001, for waist circumference 94-102 and ≥102 cm, respectively]. Incident
81secondary hypogonadal men experienced new/worsening sexual symptoms [low libido, erectile dysfunction
82and 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 waist
84circumference [OR=1.93(1.01;3.70)p=0.048], younger age [<60yr OR=2.32(1.12;4.82);p=0.024] and higher
85education [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 secondary
87hypogonadism, which is frequently reversible with weight loss.
88
11 3 12 13 14 89Introduction
90After the third decade T decreases in men by 0.4-2% per year (1). Besides ageing, other risk factors
91contribute substantially to the T decline, particularly and irrespective of age, obesity (1,2). There is also
92evidence suggesting that low T can promote fat accumulation (3) suggesting a bi-directional relationship
93between obesity and low T. Longitudinal data from the European Male Ageing Study (EMAS) showed that
94weight 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 associated
96with 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 sexual
98dysfunction (6). To better understand the natural history and clinical significance of sHG, it is important to
99further investigate longitudinally the role of obesity, relative to other potential risk factors, in predicting the
100development of and recovery from sHG.
101Symptoms of androgen deficiency in the presence of low T provide the diagnostic cornerstone of the
102syndrome of hypogonadism (7). Late-onset hypogonadism (LOH) has been stringently defined by us as
103subnormal T associated with three sexual symptoms (5,8). However, the cross-sectional association between
104low 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 impaired
107physical activity (11). Confirming the appearance of these symptoms with the development of biochemical
108hypogonadism and/or their resolution following recovery to eugonadism (EUG) would support their
109relevance as specific clinical markers of androgen deficiency, important in the diagnostic workup of men
110with low T.
111
112The aim of the study was to identify predictors of, and symptoms associated with incident sHG (isHG) and
113recovery from sHG (rsHG) in middle-aged and older men from the general population.
114
115Materials and methods
116Participants and study design
15 4 16 17 18 117The EMAS design and methods have been previously described (12,13). Briefly, an age-stratified sample of
1183,369 men aged 40–79 (mean±SD:60±11) years were recruited from population registers in eight European
119centres: Manchester (UK), Leuven (Belgium), Malmö (Sweden), Tartu (Estonia), Lodz (Poland), Szeged
120(Hungary), Florence (Italy) and Santiago de Compostela (Spain). Participants attended research clinics at
121baseline and 4.3 years later (range 3.0–5.7 years) for follow-up assessments (12,13). During this period, 193
122men died, 334 were lost to follow-up and 106 were institutionalised or became too frail. Ethical approval for
123the study was obtained according to institutional requirements in each centre. All participants provided
124written, informed consent. They completed questionnaires at both baseline and follow-up (12,13) about
125smoking, alcohol consumption and currently treated comorbidities (1). Anthropometric measurements,
126Reuben’s physical performance test (PPT) and psychomotor processing speed (Digit Symbol Substitution
127Test (DSST)) were performed according to standardised methods (12,13). Physical, sexual and psychological
128symptoms were determined from responses to the MOS 36-item Short-Form health survey (SF36), the
129EMAS Sexual Function Questionnaire and the Beck Depression Inventory (BDI), respectively.
130Hormone measurements
131Single, fasting morning (before 10:00 h) venous blood samples were obtained at baseline and follow-up. T
132was measured by liquid chromatography–tandem mass spectrometry (LC–MS/MS), with paired baseline and
133follow-up samples analysed simultaneously. LH, FSH and SHBG were measured by the E170 platform
134electrochemiluminescence immunoassay (Roche Diagnostics). Free T was calculated using the Vermeulen
135formula (14). Intra- and inter-assay coefficients of variation (CV) were: T 4.0 and 5.6%; SHBG 1.7 and
1363.2%, LH 1.9 and 3.0% and FSH 1.8 and 5.3%, respectively. The lower limit of total T measurement was
1370.17 nmol/l (0.05 ng/ml). Insulin was assayed using chemiluminescence (CVs: 3.9% and 5%). Biochemistry
138and haematology parameters were performed with standardized measurements, undertaken in hospital
139laboratories in each centre. Insulin resistance was calculated using the homoeostasis model assessment of
140insulin resistance [HOMA-IR=fasting insulin (U/ml)×fasting glucose (mmol/l)/22.5] (15).
141Gonadal status
142Participants 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) – EUG
19 5 20 21 22 144at baseline and follow-up, (b) incident sHG (isHG) – EUG at baseline and sHG at follow-up, (c) persistent
145sHG (psHG) – sHG at baseline and follow-up, and (d) rsHG – sHG at baseline and EUG at follow-up.
146Statistical analysis
147Baseline differences between isHG and pEUG and between rsHG and psHG in hormone levels,
148anthropometrics, biochemistry, symptoms, health and lifestyle measures were initially evaluated by
149Student’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 hierarchical
151study design (individuals nested within centre). The relationships between gonadal status and putative
152predictors were assessed using multilevel binary logistic regression models, where gonadal status was the
153outcome, 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 [low
156(compulsory education only), medium (non-compulsory education below university level) or high (university
157education)], Physical Activity Scale for the Elderly ((PASE) score ≤78 vs. >78), Chronic widespread pain
158(yes/no), marital status (no partner, having a partner but not living together or having a partner and living
159together), comorbidity (presence/absence of at least one self-reported disorder), BMI (<25 kg/m 2, 25–29.9
160kg/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 logistic
162regression models with symptoms, dichotomized as stable or new/worsened, as the outcome, when assessing
163outcomes of isHG, and as stable or resolved/improved, when assessing outcomes of rsHG. A symptom was
164defined as new when absent at baseline and present at follow-up and worsened when present at baseline but
165with a lower severity grading than at follow-up. A symptom was defined as resolved when present at
166baseline and absent at follow-up and improved when present at follow-up with a lower severity grading than
167at baseline.
168Differences in clinical characteristics between isHG and pEUG or rsHG and psHG at baseline and changes
169over time were investigated by multiple logistic regression models adjusted for age (as a continuous
170variable), 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 or
173percentage 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 rsHG
175predictor 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 conducted
178using SPSS for Windows 20.1 (IBM, Armonk, NY, USA).
179
180Results
181Natural history of secondary hypogonadism (sHG)
182Of the 3,369 men that participated in EMAS (Figure 1): 193 were excluded at baseline because of medical
183conditions (known pituitary-testicular diseases and medications affecting T); 165 died during the follow-up
184period; 93 were institutionalised or too frail to attend for follow-up and 314 were lost to follow-up for other
185reasons. Another 162 were excluded at follow-up because of medical conditions/medications, and 121 were
186excluded 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 8.2
188and 11.3%, compared to the entire cohort’s rates of 5.2% and 9.9%, respectively. In the analytical sample of
1892,268 men, 1,909 were pEUG, 140 isHG, 123 psHG and 96 rsHG (Figure 1). The prevalence of sHG at
190follow-up was 11.0% and the incidence of sHG from EUG was 6.28% in 4.3 years or 155.9 per 10,000 per
191year or 1.6% per annum. The recovery rate from sHG to EUG was 30.2% (96/318) or 42.9% (96/224
192excluding 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 were
194older, had lower free T, higher SHBG and gonadotropins, but not significantly different total T levels and
195reported more diabetes mellitus, cardiovascular diseases and worse physical performance (Supplementary
196table 1). Conversely, subjects who were lost to follow-up for other reasons were similar to the analytical
197group, except for a higher prevalence of smoking and metabolic syndrome (MetS) and lower psychomotor
198processing speed.
199 Characteristics of iSHG
27 7 28 29 30 200Lower mean total T, free T, SHBG, LH and FSH levels were already apparent in iSHG men compared to
201pEUG, at baseline; these differences were replicated and amplified at follow-up (Table 1). isHG men were
202overweight/obese at baseline, with higher prevalence of comorbidities and MetS; these factors increased
203further at follow-up. isHG men also showed differences in baseline and follow-up metabolic profiles with
204lower 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 an
206independent predictor of isHG (Figure 2A). Substituting WC for BMI categories showed that increased WC
207was 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 and
208WC>102 cm respectively] and that older men (≥70yr) demonstrated a significantly lower predisposition to
209develop 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 found
211between the variables in the model.
212Prevalence of symptoms at baseline and follow-up, as well as new/worsening symptoms during follow-up
213are shown in Table 1. Men with isHG, compared with pEUG, did not show any difference in prevalence of
214symptoms at baseline before or after adjustment (Table 2, Figure 3A). isHG was associated with a higher
215prevalence of decreased libido at follow-up and, although just missing statistical significance, the prevalence
216of erectile dysfunction (ED) and infrequent morning erections were higher than pEUG at follow-up (Table 2
217and Figure 3B). isHG, however, was significantly associated with the development or worsening of all three
218sexual symptoms and one physical symptom (impaired vigorous activity) (Table 2). Incremental adjustments
219for potential confounders (Table 2) showed that isHG maintained its association only with new/worsening
220sexual symptoms (Figure 3C).
221Compared with pEUG, isHG subjects had significantly higher total cholesterol at baseline (Table 3). In
222addition, isHG was associated with a significant increase in HDL-cholesterol (Table 3). The apparent
223relationship 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 did
225not differ from pEUG at baseline, but they showed a significant decrease in feeling of physical well-being
226(SF36-physical component score), and deterioration in PPT rating (Table 3).
227
31 8 32 33 34 228Characteristics of rsHG
229At baseline, rsHG subjects had higher SHBG and total T levels as compared with psHG (Table 1). rsHG men
230had a more favourable baseline metabolic profile, with lower triglycerides and a lower prevalence of MetS
231than psHG. They also showed lower weight, BMI and WC. rsHG was independently predicted by being
232younger 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). A
234higher level of education predicted rsHG [OR=2.11 (1.05;4.26);p=0.037] (Figure 2B and 2D). Weight
235reduction (≥5%) during follow-up, when substituted for BMI, was also a predictor for rsHG
236[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 during
238follow-up in psHG and rsHG are shown in Table 1. No significant association was found between rsHG with
239either baseline or follow-up prevalence or recovery/improvement of sexual, physical or psychological
240symptoms (Figure 3D). rsHG, compared with psHG, had significantly lower total cholesterol and
241triglycerides at baseline and a significant decrease in insulin during follow-up (Table 3), whereas no
242significant difference was found for physical and psychological function.
243
244Discussion
245The longitudinal data in this observational cohort of older men from the general population highlight the role
246of obesity and weight gain as the most important predictors for developing sHG, showing for the first time
247that isHG is associated with appearance or worsening of sexual symptoms only. Another new finding is that
248sHG 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 isHG
251As previously shown by cross-sectional data from EMAS, BMI is an important correlate of sHG (5). In this
252longitudinal evaluation, we are able to confirm that BMI predicts isHG. Our finding of obesity as a
253determinant for T decline, independent of LH, confirms earlier longitudinal results (16,17). The association
254between obesity and HG is complex and poorly understood. Obesity can induce peripheral and central
255insulin resistance (18), pro-inflammatory cytokine production (TNFα and IL-6) from adipocytes (19) and
35 9 36 37 38 256central nervous system endocannabinoid release (20) that can induce down-regulation of hypothalamic
257function. In addition, adipocytokines such as leptin and adiponectin have been shown to modulate GnRH and
258gonadotropin secretion (21) and to influence testicular T production (22). Conversely, the suggested role for
259an 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), their
261estradiol 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 data
263from 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 high
265gonadotropin (as in older men) are less likely to suppress LH to values below the threshold used to define
266sHG. Men attending both phases of the study are healthier as compared with those who did not (see
267Supplementary table 1). It is therefore conceivable that among those attending for follow-up, a survival bias
268may have selected healthier older men who are less prone to develop sHG (24).
269
270Developing sHG: clinical features
271In this study, development of sHG was associated, independently of BMI, comorbidities and lifestyle, with
272new or worsening sexual symptoms but not physical or psychological ones. This is consistent with our
273previous cross-sectional analyses (8) indicating that these three sexual symptoms are the most specific
274subjective features associated with low T. In addition to confirming the substantial baseline prevalence
275(22.7-48.5%) of sexual symptoms, occurrence of new or worsening symptoms in the pEUG men is not
276negligible (18%), albeit at a lower rate than in isHG men (25.6–28.1%), thus accounting for the weaker
277association between isHG and increased prevalence of sexual symptoms at follow-up. This emphasises the
278importance of the co-occurrence of all three sexual symptoms for increasing the probability of a robust
279syndromic clustering with low T (8) which serves to provide the operational definition of symptomatic HG
280or LOH. The longitudinal results, showing a specific association between the development of sHG with the
281appearance 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 whose
285new occurrence or worsening was significantly associated with isHG, until smoking and alcohol habits were
286included 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 (PPT
288rating), a significantly greater reduction of these functions was found in isHG men, even though this was not
289translated into a subjective perception of deterioration.
290
291Predictors of rsHG
292The present results show that sHG is frequently (30.2%) reversible. Reversion to eugonadism was predicted
293by lower BMI or WC, weight loss, younger age and higher education. The weight associations are
294compatible with recent evidence from general population showing that weight loss is associated with a
295proportionate increase in T levels (4,25). Thus, a >5% weight loss was associated with a significant increase
296of T levels with the maximum effect in those men who lost ≥15% of weight when LH as well T increased
297contemporaneously (4). Supervised dieting/exercise or bariatric surgery in obese men has been shown to
298increase T and LH levels proportionally to the amount of weight loss (26). Interestingly, T increase attained
299in treated subjects was higher in younger patients (26). We found, in addition to lower weight, that younger
300age was an independent predictor of rsHG suggesting that the potential for weight loss to improve
301hypothalamic-pituitary function may be eroded by adverse effects of ageing. A novel finding is that a higher
302level of education was an independent predictor of rsHG. Education is a socio-economic status surrogate and
303an important determinant of health inequality. Higher education is a protective factor for cardiovascular
304diseases and all-cause mortality (27,28). Changes in behaviour in response to health education are most
305beneficial in higher socio-economic groups (27-29) which may translate into improved metabolic status and
306avoidance of obesity. Taken together, these results strongly suggest that sHG or functional hypothalamic
307suppression 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 older
309men, 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 relationships
311between BMI or weight loss with rsHG (data not shown), suggesting that the observed weight loss in those
43 11 44 45 46 312obese middle-aged men (mean age 56 yr) with rsHG may well have been intentional and that the
313concomitant rise in T is part of the overall, positive health outcome.
314
315 Recovering from sHG: clinical features
316In this study, the anticipated association between rsHG and resolution/improvement of symptoms was not
317found. There are a number of possible explanations. The relatively small sample size may not provide
318sufficient statistical power to detect small differences between psHG (n=123) and rsHG (n=96), with a
319minority only (2-11 men) showing symptomatic improvements. Both groups are subjected to uncontrolled
320multiple 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 sustained
322improvement to transmute into subjective symptomatic recovery. Randomized controlled trials of T
323replacement therapy demonstrating improvements in sexual function (30), physical strength (31) and
324depressive symptoms (32) usually show a 2-fold increase of T levels into the mid-normal physiological range
325during treatment, for a minimum of 24 weeks. The spontaneous rise in T levels observed in our rsHG
326subjects is relatively small by comparison (9.2 nmol/L at baseline increasing to 13.3 nmol/L at follow-up or a
32745% increment) and may not be sufficient to drive improvements or resolution of sexual symptoms. Given
328the high prevalence of sexual symptoms irrespective of the concentration of circulating T, a further
329explanation could be that important non-hormonal (e.g. psychosocial and relational) factors contribute to the
330persistence of symptoms, even after restoration of normal T levels .
331
332Strengths and limitations
333The strengths of this study include a large unbiased sample from the general population, the prospective
334design providing non-interventional longitudinal data to investigate the natural history and predictors of
335hypogonadism 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 analysed
337simultaneously. Limitations in EMAS have been described previously (13). The study interval of 4.3 years
338may be relatively short for capturing the more subtle changes in signs and symptoms of HG in an
339observational 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 measurement
341only was available at each time point. However, T is a stable analyte (33) and single measurements of T on
342morning samples, can provide representative and reliable data in large epidemiological studies such as the
343EMAS.
344
345Conclusions
346Our longitudinal data showed that overweight, obesity or weight gain predisposed older men to develop
347sHG. Older men were at lower risk. Development of sHG was associated with the appearance of new or
348worsening sexual, but not physical and psychological symptoms. sHG frequently remits spontaneously; this
349is predicted by lower BMI or WC or weight loss, as well as younger age and higher education. Biochemical
350reversal of sHG to EUG however was not accompanied by a significant symptomatic improvement. Further
351studies are indicated to corroborate and extend the present results.
51 13 52 53 54 352ACKNOWLEDGEMENTS
353The European Male Aging Study is funded by the Commission of the European Communities Fifth
354Framework Program “Quality of Life and Management of Living Resources” Grant QLK6-CT-2001-00258
355and facilitated by the Manchester Biomedical Research Centre and the NIHR Greater Manchester: Clinical
356Research Network. Additional support was also provided by Arthritis Research UK and the National Institute
357for Health Research and the Manchester Biomedical Research Centre. The Principal Investigator of EMAS is
358Professor Frederick Wu, MD; Andrology Research Unit, University of Manchester, Manchester, UK. The
359authors wish to thank the men who participated in the eight countries, the research/nursing staff in the eight
360centres: C Pott (Manchester), E Wouters (Leuven), M Nilsson (Malmö), M del Mar Fernandez (Santiago de
361Compostela), M Jedrzejowska (Łódź), H-M Tabo (Tartu), A Heredi (Szeged) for their data collection, and C
362Moseley (Manchester) for data entry and project co-ordination. Dr. D Vanderschueren is a senior clinical
363investigator supported by the Clinical Research Fund of the University Hospitals Leuven, Belgium.
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55 14 56 57 58 380References
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71 18 72 73 74 474Legends to figures
475Figure 1. Study flow-chart showing exclusion of subjects and distribution of study sample by gonadal status
476HG=hypogonadism; pEUG=persistent eugonadal at baseline; isHG=incident secondary hypogonadism;
477psHG=persistent secondary hypogonadism; rsHG=recovery from secondary hypogonadism
478
479Figure 2
480A. Predictors of incident secondary hypogonadism (sHG). Data are derived from multilevel binary regression
481models, using centre as a random-effect covariate and age (categorized into 10 years age bands), smoking
482status (current smoker – yes/no), alcohol intake (alcohol consumption for ≥5 per week vs. less), education
483level [low (compulsory education only), medium (non-compulsory education below university level) or high
484(university education)], Physical Activity Scale for the Elderly (PASE, score ≤78 and >78), Chronic
485widespread pain (yes/no), marital status (no partner, having a partner not living together or having a partner
486and living together), comorbidity (presence/absence of at least one self-reported disorder) and body mass
487index (BMI) [<25 kg/m2, 25–29.9 kg/m2, and ≥30 kg/m2] as fixed-effect predictors. Gonadal status was the
488outcome 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 a
491random-effect covariate and age [dichotomized into age <60 and age ≥60 years (yr)], smoking status (current
492smokers – yes/no), alcohol intake (alcohol consumption for ≥5 per week vs. less), education level [low and
493medium (completed non compulsory education but lower than university level) vs. high (university
494education)], 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 secondary
497hypogonadal 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 a
499random-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 (compulsory
501education 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) [<94
505cm, 94-102 cm, and ≥102 cm] as fixed-effect predictors. Gonadal status was the outcome with the persistent
506eugonadal 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 a
508random-effect covariate and age [dichotomized into age <60 and age ≥60 years (yr)], smoking status (current
509smoker – yes/no), alcohol intake (alcohol consumption for ≥5 per week vs. less), education level [low and
510medium (completed non compulsory education but lower than university level) vs. high (university
511education)], 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 secondary
514hypogonadal group being the referent category. The odd ratios are shown on a log-scale.
515* p<0.05; *** p<0.0001
516
517Figure 3. Upper panels: Association between incidence of secondary hypogonadism and baseline
518prevalence (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 alcohol
520intake], using the group of persistent eugonadal subjects as referent category. The odd ratios are shown on a
521log-scale. Lower panels: Association between recovery from secondary hypogonadism and baseline (Panel
522D) or follow-up (Panel E) prevalence or recovery/improvement (Panel F) of hypogonadism-related
523symptoms [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 shown
525on a log-scale.
526* p<0.05; ** p<0.01
79 20 80