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GLO:FSQE/03oct22:andr13244-fig-0002.jpg PHOTO (COLOR): 2 Cover page of the EAA Membership list 1997, statutes and andrology centers. gl The EAA had become a member of the International Society of Andrology (ISA) and had been affiliated with the European Federation of Endocrine Societies (EFES). EAA Clinical Andrologist examination An examination to certify trainees as EAA-certified andrologists was established in 1997 and regular sessions were scheduled annually, mainly concurrently with the European Testis Workshop or the European Congress of Andrology. Thanks to the EAA secretary, Ewa Rajpert-De Meyts, our members have been constantly informed about EAA and andrology-related issues through regular EAA Newsletters and the monthly Literature Alert. Keywords: EAA; EAA Schools; International Journal of Andrology; European Congress of Andrology EN EAA EAA Schools International Journal of Andrology European Congress of Andrology 4 9 6 11/29/22 20221003 NES 221003 THE EARLY DAYS (by Eberhard Nieschlag) GRAPH During the second half of the 20th century andrology, the discipline of male reproductive health, gained steadily in relevance as a basic and clinical field.1,2 National societies of andrology were founded in several countries in the 1970s and 1980s (e.g., Scandinavia 1973, USA 1975, Germany 1975, Italy 1976). [Extracted from the article]

Although estrogens have been always referred as female hormones, the deep involvement of these steroids in the development and control of male reproductive functions is only recently emerging. After a brief overview of estrogen effects on male different systems and organs, the present review will focus on estrogens as potential hormones in male reproduction. The present knowledge on the structure and regulation of estrogen receptor (ER) genes will be summarized and the expression pattern of the different isoforms of ERs in male reproductive system and of aromatase (Ar), the enzyme responsible for conversion of androgens into estrogens, will be reported, paying particular attention to distribution in human tissue. In addition to the description of the well-known genomic action exerted by estrogens through the classical nuclear receptors, alternative intracellular mechanisms of action of these hormones will be overviewed, with particular attention to the recently described so called nongenomic ones. In particular, recent data supporting evidences of nongenomic action of estrogens on human spermatozoa will be discussed. Possible cross-talks between the different signaling pathways will be taken into account. Comparison between phenotype in knockout mice for the genes encoding ERs and Ar and patients carrying congenital estrogen deficiency due to inactivating mutations of Ar gene or to estrogen resistance has been of fundamental importance in our understanding of the role of estrogens in male fertility. Finally, the requirement of estrogens in physiological development of male reproductive system will be described pointing out the possible deleterious effects on male reproductive structures exerted by abnormal exposure of male fetuses and adults to these hormones. [Copyright &y& Elsevier]

Features the andrology center at the University of Catania in Sicily, Italy. Objectives of center; List of institutions collaborated by the center; Method of managing the andrological patients in the center.

The involvement of voltage-dependent calcium channels in the biological effects exerted by progesterone (P) on human spermatozoa is still a controversial issue. We have investigated the involvement of T-type calcium channels [voltage-operated calcium channels (VOCCT)] in two biological functions of human sperm, responsiveness to P and capacitation, by employing three different pharmacological antagonists of VOCCT, namely mibefradil (Ro 5967), pimozide and amiloride. Intracellular calcium [Ca[sup 2+]][sub i] increase in response to P was essentially unaffected by pre-treatment with mibefradil and pimozide at concentrations previously shown to prevent [Ca[sup 2+]][sub i] increase in response to zona proteins. Amiloride could not be tested in these experiments because it was found to interfere with fura-2 fluorescence. The increase in tyrosine phosphorylation stimulated by P in a protein of about 97 kDa was unaffected by the three antagonists. Acrosome reaction (AR) induced by P was also unaffected by mibefradil or pimozide but was significantly inhibited by amiloride at high concentrations (100 and 500 but not 10 μM). At 100 and 500 μM amiloride also inhibited Na/H exchanger as assessed by a fluorimetric method. We conclude that VOCCT are not involved in calcium increase and AR stimulated by P in human sperm. We next investigated the effect of the three VOCCT inhibitors on sperm capacitation by evaluating tyrosine phosphorylation and AR in basal conditions and in response to P. We found that the presence of pimozide and amiloride during capacitation stimulated a higher increase of tyrosine phosphorylation, whereas mibefradil was less effective. The ability of P to induce the AR, considered an index of occurrence of capacitation, was not affected by pimozide and mibefradil, whereas was inhibited by amiloride at concentrations that inhibit Na/H exchanger. In conclusion, our results do not support a major role of low-voltage-activated calcium channel... [ABSTRACT FROM AUTHOR]

Background erectile dysfunction is associated with mortality, whereas the association between low testosterone (T) and higher mortality remains controversial. Sexual dysfunction and low T often coexist, but the relative importance of sexual symptoms versus low T in predicting mortality is not known. We studied the interrelationships between sex steroids and sexual symptoms with all-cause mortality in a large prospective cohort of European men. Design survival status was assessed in 1,788 community-dwelling men, aged 40–79, who participated in the European Male Ageing Study (EMAS). Sexual symptoms were evaluated via a validated questionnaire (EMAS-SFQ). Sex steroids were measured by mass spectrometry. Cox proportional hazard models were used to study the association between hormones, sexual symptoms and mortality. Results about 420 (25.3%) men died during a mean follow-up of 12.6 ± 3.1 years. Total T levels were similar in both groups, but free T was lower in those who died. Men with three sexual symptoms (erectile dysfunction, reduced morning erections and lower libido) had a higher mortality risk compared with men with none of these symptoms (adjusted hazard ratio (HR) and 95% confidence intervals: 1.75 (1.28–2.40, P  = 0.001)). Particularly, erectile dysfunction and poor morning erections, but not lower libido, were associated with increased mortality (HR 1.40 (1.13–1.74, P  = 0.002), 1.28 (1.04–1.59, P  = 0.023) and 1.12 (0.90–1.39, P  = 0.312), respectively). Further adjusting for total T, free T or oestradiol did not influence the observed risk. Conclusions sexual symptoms, in particular erectile dysfunction, predict all-cause mortality independently of sex steroids and can be an early warning sign of a poor health status. [ABSTRACT FROM AUTHOR]

Male hypogonadism is a condition characterized by inadequate testicular production of sex steroids and sperms; however, the term is more commonly used to identify testosterone (T) deficiency. When fertility is not desired, T replacement therapy (TRT) is the gold standard. To review the pathogenesis of male hypogonadism and the available preparations for TRT, along with the main clinical outcomes. A systematic search of published evidence was performed using Medline (1969 to September 2010). Data from a consecutive series of subjects attending our Andrology Unit were also provided to stress the clinical correlates of low T. Inventories available for detecting hypogonadism (including ANDROTEST) were overviewed. The most important studies regarding the pathogenesis of male hypogonadism and the preparations for its treatment were reviewed. To review TRT outcomes, only meta-analytic studies were considered. The goals of TRT are to alleviate clinical symptoms and to restore serum T levels to the mid-normal range, without significant side effects or safety concerns. Different T formulations have been approved. TRT is associated with a reduction of fat mass, an increase of lean mass, and a possible positive effect on lipid profile and glycometabolic control. Bone density and depressive symptoms are improved by TRT, while effects on cardiovascular risk and frailty are more controversial. No increase of prostate cancer and prostate-related problems has been reported so far. TRT, alone or in combination with phosphodiesterase type 5 inhibitors, is considered the first-line therapy in hypogonadal subjects with erectile dysfunction. T deficiency is highly prevalent in the aging male and represents a sign of physical and sexual frailty. The significance of low T in elderly men has yet to be completely clarified. Large, prospective intervention trials will help solve this dilemma. [ABSTRACT FROM AUTHOR]

Introduction. Limited information is available concerning the general and sexual health status of European men. Aim. To investigate the age-related changes in general and sexual health in middle-aged and older men from different countries of the European Union. Methods. This is a cross-sectional multicenter survey performed on a sample of 3,369 community-dwelling men aged 40–79 years old (mean 60 ± 11 years). Subjects were randomly selected from eight European centers including centers from nontransitional (Florence [Italy], Leuven [Belgium], Malmö[Sweden], Manchester [United Kingdom], Santiago de Compostela [Spain]) and transitional countries (Lodz [Poland], Szeged [Hungary], Tartu [Estonia]). Main Outcome Measures. Different parameters were evaluated including the Beck's Depression Inventory for the quantification of depressive symptoms, the Short Form-36 Health Survey for the assessment of the quality of life (QoL), the International Prostate Symptom Score for the evaluation of lower urinary tract symptoms, and the European Male Ageing Study sexual function questionnaire for the study of sexual function. Results. More than 50% of subjects reported the presence of one or more common morbidities. Overall, hypertension (29%), obesity (24%), and heart diseases (16%) were the most prevalent conditions. Around 30% of men reported erectile dysfunction (ED) and 6% reported severe orgasmic impairment, both of which were closely associated with age and concomitant morbidities. Only 38% of men reporting ED were concerned about it. Furthermore, concern about ED increased with age, peaking in the 50–59 years age band, but decreased thereafter. Men in transitional countries reported a higher prevalence of morbidities and impairment of sexual function as well as a lower QoL. Conclusion. Sexual health declined while concomitant morbidities increased in European men as a function of age. The burden of general and sexual health is higher in transitional countries, emphasizing the need to develop more effective strategies to promote healthy aging for men in these countries. Corona G, Lee DM, Forti G, O'Connor DB, Maggi M, O'Neill TW, Pendleton N, Bartfai G, Boonen S, Casanueva FF, Finn JD, Giwercman A, Han TS, Huhtaniemi IT, Kula K, Lean MEJ, Punab M, Silman AJ, Vanderschueren D, Wu FCW, and EMAS Study Group. Age-related changes in general and sexual health in middle-aged and older men: Results from the European Male Ageing Study (EMAS). J Sex Med 2010;7:1362–1380. [ABSTRACT FROM AUTHOR]

Introduction. Assessment of male sexual dysfunction has been the focus of substantial scientific effort. Less research has focused on the development of instruments for the measurement of sexual functioning in aging men. Aims. The aims of this study were: (i) to characterize the psychometric properties of a new brief, reliable, and valid measure of male sexual functioning for use in a large population survey of middle-aged and elderly European men; and (ii) specifically, to determine whether the new instrument, the European Male Ageing Study–sexual function questionnaire (EMAS–SFQ), discriminates between men with high and low levels of circulating testosterone (T) (total T, free T, and bioavailable T). Method. One thousand six hundred men aged 40–79 years completed the self-administered EMAS–SFQ, the Beck depression inventory, and provided a blood sample for assessment of sex hormones. Eighty-five men aged 35–74 years completed the EMAS–SFQ twice, 2 weeks apart to examine the test–retest reliability of the instrument. Main Outcome Measures. Scores on the EMAS–SFQ in relation to age and T levels. Results. Principal component analysis showed that the EMAS–SFQ had four distinct domains (overall sexual functioning [OSF], masturbation, sexual functioning-related distress, and change in sexual functioning). The instrument demonstrated excellent internal and test–retest reliability, as well as convergent, divergent, and discriminant validity. Men with the lowest levels of total, free, and bioavailable T reported lower OSF scores compared to men with the highest T levels. Conclusions. The EMAS–SFQ is a valid and reproducible instrument, sensitive to age and T levels. It should be suitable for the assessment of sexual health in population samples of men in epidemiological studies of aging. O'Connor DB, Corona G, Forti G, Tajar A, Lee DM, Finn JD, Bartfai G, Boonen S, Casanueva FF, Giwercman A, Huhtaniemi IT, Kula K, O'Neill TW, Pendleton N, Punab M, Silman AJ, Vanderschueren D, Wu FCW, and the European Male Ageing Study group. Assessment of sexual health in aging men in Europe: Development and validation of the European Male Ageing Study sexual function questionnaire. J Sex Med 2008;5:1374–1385. [ABSTRACT FROM AUTHOR]

Objectives. To analyse the relation between results of the Aging Males' Symptoms (AMS) questionnaire for aging males, and of quality of life (QOL) questionnaire SF-12 and cardiovascular risk factors. Methods. 1,927 men aged 55-85 years were interviewed by 56 general practitioners. During the interview the men were asked to fill in the AMS scale and the QOL questionnaire SF-12. Results. Of 1,927 men 1,806 men filled correctly the AMS questionnaire. The mean SF-12 mental index was respectively 55.9 in men with a total AMS score indicating no impairment, 50.9 mild, 42.8 moderate, and 32.8 severe impairment. The corresponding values for the physical index were 51.2, 46.7, 40.8 and 32.3. A history of diabetes was associated with an increased risk of reporting moderate/severe impairment: in relation to the total AMS score the odds ratio, (OR), of moderate/severe impairment in comparison with no impairment was 1.6 (95%CI 1.2-2.1). A history of myocardial infarction and hypertension increased the risk (respectively OR 1.4 (95%CI 1.1-18) and 1.7 (95%CI 1.2-2.4)). Conclusions. This study shows that higher AMS scores are associated with lower SF-12 indices and suggests that elevated values of the AMS score are associated with cardiovascular risk factors or diseases. [ABSTRACT FROM AUTHOR]

Background: Evidence regarding functional hypogonadism, previously referred to as 'late‐onset' hypogonadism, has increased substantially during the last 10 year. Objective: To update the European Academy of Andrology (EAA) guidelines on functional hypogonadism. Methods: Expert group of academicians appointed by the EAA generated a series of consensus recommendations according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. Results: The diagnosis of functional hypogonadism should be based on both the presence of clinical symptoms supported by repeatedly low morning fasting serum total testosterone (T) measured with a well‐validated assay, after exclusion of organic causes of hypogonadism. Lifestyle changes and weight reduction should be the first approach in all overweight and obese men. Whenever possible, withdrawal/modification of drugs potentially interfering with T production should be advised. Testosterone replacement therapy (TRT) is contraindicated in men with untreated prostate or breast cancer, as well as severe heart failure. Severe low urinary tract symptoms and haematocrit >48%‐50% represent relative contraindications for TRT. Prostate‐specific antigen and digital rectal examination of the prostate should be undertaken in men >40 years of age before initiating TRT to exclude occult prostate cancer. Transdermal T should be preferred for initiation of TRT, whereas gonadotrophin therapy is only recommended when fertility is desired in men with secondary hypogonadism. TRT is able to improve sexual function in hypogonadal men. Other potential positive outcomes of TRT remain uncertain and controversial. Conclusion: TRT can reliably improve global sexual function in men with hypogonadism in the short term. Long‐term clinical benefits, and safety of TRT in functional hypogonadism, remain to be fully documented. Clinicians should therefore explicitly discuss the uncertainties and benefits of TRT and engage them in shared management decision‐making. [ABSTRACT FROM AUTHOR]

Summary: Objective: Limited evidence supports the use of free testosterone (FT) for diagnosing hypogonadism when sex hormone–binding globulin (SHBG) is altered. Low total testosterone (TT) is commonly encountered in obesity where SHBG is typically decreased. We aimed to assess the contribution of FT in improving the diagnosis of symptomatic secondary hypogonadism (SH), identified initially by low total testosterone (TT), and then further differentiated by normal FT (LNSH) or low FT (LLSH). Design: Prospective observational study with a median follow‐up of 4.3 years. Patients: Three thousand three hundred sixty‐nine community‐dwelling men aged 40‐79 years from eight European centres. Measurements: Subjects were categorized according to baseline and follow‐up biochemical status into persistent eugonadal (referent group; n = 1880), incident LNSH (eugonadism to LNSH; n = 101) and incident LLSH (eugonadism to LLSH; n = 38). Predictors and clinical features associated with the transition from eugonadism to LNSH or LLSH were assessed. Results: The cumulative incidence of LNSH and LLSH over 4.3 years was 4.9% and 1.9%, respectively. Baseline obesity predicted both LNSH and LLSH, but the former occurred more frequently in younger men. LLSH, but not LNSH, was associated with new/worsened sexual symptoms, including low desire [OR = 2.67 (1.27‐5.60)], erectile dysfunction [OR = 4.53 (2.05‐10.01)] and infrequent morning erections [OR = 3.40 (1.48‐7.84)]. Conclusions: These longitudinal data demonstrate the importance of FT in the diagnosis of hypogonadism in obese men with low TT and SHBG. The concurrent fall in TT and FT identifies the minority (27.3%) of men with hypogonadal symptoms, which were not present in the majority developing low TT with normal FT. [ABSTRACT FROM AUTHOR]

Summary: Objective: Elevated luteinizing hormone (LH) with normal testosterone (T) suggests compensated dysregulation of the gonadal axis. We describe the natural history, risk factors and clinical parameters associated with the development of high LH (HLH, LH >9.4 U/L) in ageing men with normal T (T ≥ 10.5 nmol/L). Design, Patients and Measurements: We conducted a 4.3‐year prospective observational study of 3369 community‐dwelling European men aged 40‐79 years. Participants were classified as follows: incident (i) HLH (n = 101, 5.2%); persistent (p) HLH (n = 128, 6.6%); reverted (r) HLH (n = 46, 2.4%); or persistent normal LH (pNLH, n = 1667, 85.8%). Potential predictors and changes in clinical features associated with iHLH and rHLH were analysed using regression models. Results: Age >70 years (OR = 4.12 [2.07‐8.20]), diabetes (OR = 2.86 [1.42‐5.77]), chronic pain (OR = 2.53 [1.34‐4.77]), predegree education (OR = 1.79 [1.01‐3.20]) and low physical activity (PASE ≤ 78, OR = 2.37 [1.24‐4.50]) predicted development of HLH. Younger age (40‐49 years, OR = 8.14 [1.35‐49.13]) and nonsmoking (OR = 5.39 [1.48‐19.65]) predicted recovery from HLH. Men with iHLH developed erectile dysfunction, poor health, cardiovascular disease (CVD) and cancer more frequently than pNLH men. In pHLH men, comorbidities, including CVD, developed more frequently, and cognitive and physical function deteriorated more, than in pNLH men. Men with HLH developed primary hypogonadism more frequently (OR = 15.97 [5.85‐43.60]) than NLH men. Men with rHLH experienced a small rise in BMI. Conclusions: Elevation of LH with normal T is predicted by multiple factors, reverts frequently and is not associated with unequivocal evidence of androgen deficiency. High LH is a biomarker for deteriorating health in aged men who tend to develop primary hypogonadism. [ABSTRACT FROM AUTHOR]

Purpose: Although lower levels of vitamin D have been related to poor cognitive functioning and dementia in older adults, evidence from longitudinal investigations is inconsistent. The objective of this study was to determine whether 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)D] levels are associated with specified measures of cognitive decline in ageing men. Methods: The European Male Ageing Study (EMAS) followed 3369 men aged 40-79 over 4.4 years. 25(OH)D levels at baseline were measured by radioimmunoassay, and 1,25(OH)D levels were obtained with liquid chromatography-tandem mass spectrometry. Visuoconstructional abilities, visual memory, and processing speed at baseline and follow-up were assessed using the Rey-Osterrieth Complex Figure Test (ROCF), Camden Topographical Recognition Memory (CTRM), and the Digit Symbol Substitution Test (DSST). Results: Following attritions, a total of 2430 men with a mean (SD) age of 59.0 (10.6) were included in the analyses. At baseline, the mean 25(OH)D concentration was 64.6 (31.5) nmol/l, and mean 1,25(OH)D level was 59.6 (16.6) pmol/l. In age-adjusted linear regression models, high 25(OH)D concentrations were associated with a smaller decline in the DSST ( β = 0.007, p = 0.020). Men with low 25(OH)D levels (<50 nmol/l) showed a greater decline in the CTRM compared to men with higher (≥75 nmol/l) levels ( β = −0.41, p = 0.035). However, these associations disappeared after adjusting for confounders such as depressive symptoms, BMI, and comorbidities. There was no indication of a relationship between 1,25(OH)D and decline in cognitive subdomains. Conclusion: We found no evidence for an independent association between 25(OH)D or 1,25(OH)D levels and visuoconstructional abilities, visual memory, or processing speed over on average 4.4 years in this sample of middle-aged and elderly European men. [ABSTRACT FROM AUTHOR]

Background: frailty is associated with an increased risk of fragility fractures. Less is known, however, about the association between frailty and bone health. Methods: men aged 40-79 years were recruited from population registers in eight European centres for participation in the European Male Aging Study. Subjects completed a comprehensive assessment which included quantitative ultrasound (QUS) scan of the heel (Hologic-SAHARA) and in two centres, dual-energy bone densitometry (dual-energy x-ray absorptiometry, DXA). Frailty was defined based on an adaptation of Fried's phenotype criteria and a frailty index (FI) was constructed. The association between frailty and the QUS and DXA parameters was determined using linear regression, with adjustments for age, body mass index and centre. Results: in total, 3,231 subjects contributed data to the analysis. Using the Fried categorisation of frailty, pre-frail and frail men had significantly lower speed of sound (SOS), broadband ultrasound attenuation (BUA) and quantitative ultrasound index (QUI) compared to robust men (P < 0.05). Similar results were seen using the FI after categorisation into 'high', 'medium' and 'low' levels of frailty. Using the Fried categorisation, frail men had lower femoral neck bone mineral density (BMD) compared to robust men (P < 0.05), but not lower lumbar spine BMD. Using the FI categorisation, a 'high' level of frailty (FI > 0.35) was associated with lower lumbar spine BMD (P < 0.05) when compared to those with low (FI < 0.2), but not lower femoral neck BMD. When analysed as a continuous variable, higher FI was linked with lower SOS, BUA and QUI (P < 0.05). Conclusions: optimisation of bone health as well as prevention of falls should be considered as strategies to reduce fractures in frail older people. [ABSTRACT FROM AUTHOR]

Sperm cryopreservation is widely used by cancer patients undergoing chemo- or radiotherapy. Evidence suggests that IVF outcome with cryopreserved spermatozoa from cancer patients is less successful. To determine whether sperm DNA fragmentation (SDF) is involved in the lower fertilising ability of cryopreserved spermatozoa of cancer patients, SDF was evaluated in thawed spermatozoa from 78 men affected by different cancers and 53 men with noncancer pathologies. SDF was assessed by the terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL), propidium iodide (PI), flow cytometry procedure, which allows determination of two different cell populations (PIbrighter and PIdimmer) and thus to determine the percentage of DNA fragmented sperm in both. PIdimmer spermatozoa are totally unviable, whereas PIbrighter spermatozoa with SDF may be motile and morphologically normal, having higher biological relevance in the reproductive process. We found that the proportion of DNA fragmented PIbrighter cells was significantly higher in thawed spermatozoa from cancer than non-cancer patients. Moreover, a positive correlation was found between the degree of DNA fragmentation and sperm motility in the PIbrighter population of spermatozoa from cancer patients that wasn't seen in non-cancer patients. The results of the present study suggest that higher SDF levels may contribute to the lower IVF success of cryopreserved spermatozoa from cancer patients and that evaluation of SDF could complement genetic counselling as part of the routine management of cancer patients who seek fertility preservation. [ABSTRACT FROM AUTHOR]

Objective In ageing men, the incidence and clinical significance of testosterone (T) decline accompanied by elevated luteinizing hormone ( LH) are unclear. We describe the natural history, risk factors and clinical features associated with the development of biochemical primary hypogonadism ( PHG, T < 10·5 nmol/l and LH>9·4U/l) in ageing men. Design, Patients and Measurements A prospective observational cohort survey of 3,369 community-dwelling men aged 40-79 years, followed up for 4·3 years. Men were classified as incident (i) PHG (eugonadal [ EUG, T ≥ 10·5 nmol/l] at baseline, PHG at follow-up), persistent (p) PHG ( PHG at baseline and follow-up), pEUG ( EUG at baseline and follow-up) and reversed (r) PHG ( PHG at baseline, EUG at follow-up). Predictors and changes in clinical features associated with the development of PHG were analysed by regression models. Results Of 1,991 men comprising the analytical sample, 97·5% had pEUG, 1·1% iPHG, 1·1% pPHG and 0·3% rPHG. The incidence of PHG was 0·2%/year. Higher age (>70 years) [ OR 12·48 (1·27-122·13), P = 0·030] and chronic illnesses [ OR 4·24 (1·08-16·56); P = 0·038] predicted iPHG. Upon transition from EUG to PHG, erectile function, physical vigour and haemoglobin worsened significantly. Men with pPHG had decreased morning erections, sexual thoughts and haemoglobin with increased insulin resistance. Conclusions Primary testicular failure in men is uncommon and predicted by old age and chronic illness. Some clinical features attributable to androgen deficiency, but not others, accompanied the T decline in men who developed biochemical PHG. Whether androgen replacement can improve sexual and/or physical function in elderly men with PHG merits further study. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• Sex steroid levels are proposed to be a modifiable risk factor for cognitive ageing • We tested this hypothesis in a large-scale study of middle-aged and older men • Steroid levels did not affect cognition after adjusting for health and lifestyle • Androgen CAG repeat length did not alter hormone-cognition relationships It has been proposed that endogenous sex hormone levels may present a modifiable risk factor for cognitive decline. However, the evidence for effects of sex steroids on cognitive ageing is conflicting. We therefore investigated associations between endogenous hormone levels, androgen receptor CAG repeat length, and cognitive domains including visuoconstructional abilities, visual memory, and processing speed in a large-scale longitudinal study of middle-aged and older men. Men aged 40-79 years from the European Male Ageing Study (EMAS) underwent cognitive assessments and measurements of hormone levels at baseline and follow-up (mean = 4.4 years, SD ± 0.3 years). Hormone levels measured included total and calculated free testosterone and estradiol, dihydrotestosterone, luteinizing hormone, follicle-stimulating hormone, dehydroepiandrosterone sulphate and sex hormone-binding globulin. Cognitive function was assessed using the Rey-Osterrieth Complex Figure Copy and Recall, the Camden Topographical Recognition Memory and the Digit Symbol Substitution Test. Multivariate linear regressions were used to examine associations between baseline and change hormone levels, androgen receptor CAG repeat length, and cognitive decline. Statistical analyses included 1,827 and 1,423 participants for models investigating relationships of cognition with hormone levels and CAG repeat length, respectively. In age-adjusted models, we found a significant association of higher baseline free testosterone (β=-0.001, p =0.005) and dihydrotestosterone levels (β=-0.065, p =0.003) with greater decline on Rey-Osterrieth Complex Figure Recall over time. However, these effects were no longer significant following adjustment for centre, health, and lifestyle factors. No relationships were observed between any other baseline hormone levels, change in hormone levels, or androgen receptor CAG repeat length with cognitive decline in the measured domains. In this large-scale prospective study there was no evidence for an association between endogenous sex hormone levels or CAG repeat length and cognitive ageing in men. These data suggest that sex steroid levels do not affect visuospatial function, visual memory, or processing speed in middle-aged and older men. [ABSTRACT FROM AUTHOR]

Background: we hypothesised that chronic widespread pain (CWP), by acting as a potential stressor, may predispose to the development of, or worsening, frailty. Setting: longitudinal analysis within the European Male Ageing Study (EMAS). Participants: a total of 2,736 community-dwelling men aged 40-79. Methods: subjects completed a pain questionnaire and shaded a manikin, with the presence of CWP defined using the American College of Rheumatology criteria. Physical activity, smoking, alcohol consumption and depression were measured. Repeat assessments took place a median of 4.3 years later. A frailty index (FI) was used, with frail defined as an FI >0.35. The association between CWP at baseline and the new occurrence of frailty was examined using logistic regression; the association between CWP at baseline and change in FI was examined using negative binomial regression. Results: at baseline, 218 (8.3%) men reported CWP. Of the 2,631 men who were defined as non-frail at baseline, 112 (4.3%) were frail at follow-up; their mean FI was 0.12 (SD 0.1) at baseline and 0.15 (SD 0.1) at follow-up, with a mean change of 0.03 (SD 0.08) P ≤ 0.001. Among men who were non-frail at baseline, those with CWP were significantly more likely to develop frailty. After adjustment for age and centre, compared with those with no pain, those with CWP at baseline had a 70% higher FI at follow-up; these associations remained significant after further adjustment for smoking, body mass index, depression, physical activity and FI at baseline. Conclusion: the presence of CWP is associated with an increased risk of frailty in older European men. [ABSTRACT FROM AUTHOR]

Background: The association between low levels of vitamin D and the occurrence of chronic widespread pain (CWP) remains unclear. The aim of our analysis was to determine the relationship between low vitamin D levels and the risk of developing CWP in a population sample of middle age and elderly men.Methods: Three thousand three hundred sixty nine men aged 40-79 were recruited from 8 European centres for a longitudinal study of male ageing, the European Male Ageing Study. At baseline participants underwent assessment of lifestyle, health factors, physical characteristics and gave a fasting blood sample. The occurrence of pain was assessed at baseline and follow up (a mean of 4.3 years later) by shading painful sites on a body manikin. The presence of CWP was determined using the ACR criteria for fibromyalgia. Serum 25-hydroxyvitamin D (25-(OH) D) was assessed by radioimmunoassay. Logistic regression was used to determine the relationship between baseline vitamin D levels and the new occurrence of CWP.Results: Two thousand three hundred thirteen men, mean age 58.8 years (SD = 10.6), had complete pain and vitamin data available and contributed to this analysis. 151 (6.5%) developed new CWP at follow up and 577 (24.9%) were pain free at both time points, the comparator group. After adjustment for age and centre, physical performance and number of comorbidities, compared to those in upper quintile of 25-(OH) D ( ≥36.3 ng/mL), those in the lowest quintile (<15.6 ng/mL) were more likely to develop CWP (Odds Ratio [OR] = 1.93; 95% CI = 1.0-3.6). Further adjustment for BMI (OR = 1.67; 95% CI = 0.93-3.02) or depression (OR = 1.77; 95% CI = 0.98-3.21), however rendered the association non-significant.Conclusions: Low vitamin D is linked with the new occurrence of CWP, although this may be explained by underlying adverse health factors, particularly obesity and depression. [ABSTRACT FROM AUTHOR]

Background: low bone mineral density measured by dual-energy x-ray absorptiometry is associated with increased mortality. The relationship between other skeletal phenotypes and mortality is unclear. The aim of this study was to determine the relationship between quantitative heel ultrasound parameters and mortality in a cohort of European men. Methods: men aged 40-79 years were recruited for participation in a prospective study of male ageing: the European Male Ageing Study (EMAS). At baseline, subjects attended for quantitative ultrasound (QUS) of the heel (Hologic—SAHARA) and completed questionnaires on lifestyle factors and co-morbidities. Height and weight were measured. After a median of 4.3 years, subjects were invited to attend a follow-up assessment, and reasons for non-participation, including death, were recorded. The relationship between QUS parameters (broadband ultrasound attenuation [BUA] and speed of sound [SOS]) and mortality was assessed using Cox proportional hazards model. Results: from a total of 3,244 men (mean age 59.8, standard deviation [SD] 10.8 years), 185 (5.7%) died during the follow-up period. After adjusting for age, centre, body mass index, physical activity, current smoking, number of co-morbidities and general health, each SD decrease in BUAwas associated with a 20% higher risk of mortality (hazard ratio [HR] per SD = 1.2; 95% confidence interval [CI] = 1.0-1.4). Compared with those in higher quintiles (2nd-5th), those in the lowest quintile of BUA and SOS had a greater mortality risk (BUA: HR = 1.6; 95% CI = 1.1-2.3 and SOS: HR = 1.6; 95% CI = 1.2-2.2). Conclusion: lower heel ultrasound parameters are associated with increased mortality in European men. [ABSTRACT FROM AUTHOR]

Introduction Alterations of gonadal, thyroid, and pituitary hormones, along with metabolic disorders, might be involved in causing erectile dysfunction ( ED). Aim The prevalence of endocrine abnormalities in two different cohorts from the general and the symptomatic populations of Florence was compared. Methods The first group is a general population sample derived from a Florentine spin-off of the European Male Aging Study ( EMAS cohort; n = 202); the second group is a series of n = 3,847 patients attending our clinic for ED ( UNIFI cohort). Results Both primary and secondary hypogonadism were more often observed in the UNIFI than in the EMAS cohort (2.8 vs. 0%; P < 0.05 and 18.9 vs. 8%; P < 0.001, respectively). However, only the second association retained statistical significance after adjusting for age. Compensated hypogonadism was more common in the EMAS cohort (4.4 vs. 8.1%; P < 0.05). No statistically significant difference in the prevalence of overt thyroid disorders was observed. Conversely, subclinical hyperthyroidism was more prevalent in the EMAS cohort (2 vs. 4.1%, P < 0.05). No significant difference in the prevalence of hyperprolactinemia was detected, while the prevalence of hypoprolactinemia was significantly higher in the UNIFI than in the EMAS cohort (28.2% vs. 17.8%, P = 0.001), even after the adjustment for age, BMI, and testosterone ( P = 0.001). Central obesity (waist ≥102 cm), impaired fasting glucose ( IFG), and type 2 diabetes mellitus ( T2DM) were more often detected in UNIFI patients (31.7 vs. 22.8%, P < 0.05; 44.5 vs. 33.3%, P < 0.05; 20.1% vs. 1.0%, P < 0.001 in the UNIFI and EMAS cohort, respectively), even after adjusting for age. In contrast, the prevalence of overweight and obesity did not differ between the two groups. Conclusion T2DM, IFG, central obesity, secondary hypogonadism, and hypoprolactinemia are more frequent in subjects consulting for ED than in the general population of the same geographic area. Our data suggest that these conditions could play a central role in determining consultation for ED. Maseroli E, Corona G, Rastrelli G, Lotti F, Cipriani S, Forti G, Mannucci E, and Maggi M. Prevalence of endocrine and metabolic disorders in subjects with erectile dysfunction: A comparative study. J Sex Med 2015;12:956-965. [ABSTRACT FROM AUTHOR]

Background: Hyponatremia is the most common electrolyte disorder and it is associated with increased morbidity and mortality. However, there is no clear demonstration that the improvement of serum sodium concentration ([Na+]) counteracts the increased risk of mortality associated with hyponatremia. Thus, we performed a meta-analysis that included the published studies that addressed the effect of hyponatremia improvement on mortality. Methods and Findings: A Medline, Embase and Cochrane search was performed to retrieve all English-language studies of human subjects published up to June 30th 2014, using the following words: “hyponatremia”, “hyponatraemia”, “mortality”, “morbidity” and “sodium”. Fifteen studies satisfied inclusion criteria encompassing a total of 13,816 patients. The identification of relevant abstracts, the selection of studies and the subsequent data extraction were performed independently by two of the authors, and conflicts resolved by a third investigator. Across all fifteen studies, any improvement of hyponatremia was associated with a reduced risk of overall mortality (OR=0.57[0.40-0.81]). The association was even stronger when only those studies (n=8) reporting a threshold for serum [Na+] improvement to >130 mmol/L were considered (OR=0.51[0.31-0.86]). The reduced mortality rate persisted at follow-up (OR=0.55[0.36-0.84] at 12 months). Meta-regression analyses showed that the reduced mortality associated with hyponatremia improvement was more evident in older subjects and in those with lower serum [Na+] at enrollment. Conclusions: This meta-analysis documents for the first time that improvement in serum [Na+] in hyponatremic patients is associated with a reduction of overall mortality. [ABSTRACT FROM AUTHOR]

Glucagon-Like Peptide-1 (GLP-1) receptor agonists, used as glucose-lowering drugs, also induce weight loss by inhibiting food intake. The present study was aimed at the assessment of the in vitro effects of the GLP-1 receptor agonist liraglutide on proliferation and differentiation of human adipose stem cells (ASC) obtained from subcutaneous adipose tissue of morbidly obese subjects undergoing bariatric surgery. Liraglutide (10–100 nM) significantly inhibited ASC proliferation and viability, with a maximum effect at 6 days of culture (45% and 50%, for liraglutide 10 and 100 nM, respectively); the effect was reverted by exendin 9–39. Glucose uptake was significantly reduced by liraglutide in a dose dependent manner. Treatment with liraglutide reduced intracellular lipid accumulation in differentiating ASC, together with FABP-4 mRNA expression (−18%, −23%, −46%, for 1 nM, 10 nM and 100 nM, respectively), whereas it stimulated adiponectin (APN) expression (1.86-, 2.64-, 2.28-fold increase, for 1 nM, 10 nM and 100 nM, respectively). Liraglutide exerts effects on human adipose cell precursors, inhibiting proliferation and differentiation, while stimulating the expression of the insulin-sensitizing adipokine APN. These effects could contribute to the actions of GLP-1 receptor agonists on body weight and insulin sensitivity. [ABSTRACT FROM AUTHOR]

Sperm DNA fragmentation (sDF) represents a threat to male fertility, human reproduction and the health of the offspring. The causes of sDF are still unclear, even if apoptosis, oxidative assault and defects in chromatin maturation are hypothesized. Using multicolor flow cytometry and sperm sorting, we challenged the three hypothesized mechanisms by simultaneously evaluating sDF and signs of oxidative damage (8-hydroxy, 2'-deoxyguanosine [8-OHdG] and malondialdehyde [MDA]), apoptosis (caspase activity and cleaved poly[ADP-ribose] polymerase [cPARP]) and sperm immaturity (creatine phosphokinase [CK] and excess of residual histones). Active caspases and c-PARP were concomitant with sDF in a high percentage of spermatozoa (82.6% ± 9.1% and 53.5% ± 16.4%, respectively). Excess of residual histones was significantly higher in DNA-fragmented sperm versus sperm without DNA fragmentation (74.8% ± 17.5% and 37.3% ± 16.6%, respectively, p < 0.005), and largely concomitant with active caspases. Conversely, oxidative damage was scarcely concomitant with sDF in the total sperm population, at variance with live sperm, where 8-OHdG and MDA were clearly associated to sDF. In addition, most live cells with active caspase also showed 8-OHdG, suggesting activation of apoptotic pathways in oxidative-injured live cells. This is the first investigation on the origin of sDF directly evaluating the simultaneous presence of the signs of the hypothesized mechanisms with DNA breaks at the single cell level. The results indicate that the main pathway leading to sperm DNA breaks is a process of apoptosis, likely triggered by an impairment of chromatin maturation in the testis and by oxidative stress during the transit in the male genital tract. These findings are highly relevant for clinical studies on the effects of drugs on sDF and oxidative stress in infertile men and for the development of new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Introduction In the last few years, a view that subclinical endocrine disorders represent milder forms of the clinically overt disease has emerged. Accordingly, it has been proposed that compensated hypogonadism represents a genuine clinical subset of late-onset hypogonadism. Aim The aim of the present study is to investigate the associations of compensated hypogonadism with particular clinical and psychological characteristics of male subjects complaining of sexual dysfunction. Methods After excluding documented genetic causes of hypogonadism, an unselected consecutive series of 4,173 patients consulting our unit for sexual dysfunction was studied. Compensated hypogonadism was identified according to the European Male Ageing study criteria: total testosterone ≥10.5 nmol/L and luteinizing hormone >9.4 U/L. Main Outcome Measures Several hormonal, biochemical, and instrumental (penile Doppler ultrasound) parameters were studied, along with results of the Structured Interview on Erectile Dysfunction ( SIEDY) and ANDROTEST. Results One hundred seventy (4.1%) subjects had compensated hypogonadism, whereas 827 (19.8%) had overt hypogonadism. After adjustment for confounding factors, no specific sexual symptoms were associated with compensated hypogonadism. However, compensated hypogonadism individuals more often reported psychiatric symptoms, as detected by Middlesex Hospital Questionnaire score, when compared with both eugonadal and overt hypogonadal subjects (adjusted odds ratios = 1.018 [1.005;1.031] and 1.014 [1.001;1.028], respectively; both P < 0.005). In addition, subjects with compensated or overt hypogonadism had an increased predicted risk of cardiovascular events (as assessed by Progetto Cuore risk algorithm) when compared with eugonadal individuals. Accordingly, mortality related to major adverse cardiovascular events ( MACEs), but not MACE incidence, was significantly higher in subjects with both compensated and overt hypogonadism when compared with eugonadal subjects. Conclusions The present data do not support the concept that compensated (subclinical) hypogonadism represents a new clinical entity. The possibility that subclinical hypogonadism could be a normal response of the hypothalamus-pituitary-testis axis to somatic illness should be considered. Further studies are urgently needed to clarify this latter point. Corona G, Maseroli E, Rastrelli G, Sforza A, Forti G, Mannucci E, and Maggi M. Characteristics of compensated hypogonadism in patients with sexual dysfunction. J Sex Med 2014;11:1823-1834. [ABSTRACT FROM AUTHOR]

Background: vitamin D deficiency has been associated with an increased risk of mortality, but whether this relationship is causal or linked to co-existent comorbidity and adverse life factors remains uncertain. Our objective was to determine whether endogenous 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D) and parathyroid hormone (PTH) levels predicted all-cause, cardiovascular and cancer mortality independently of health and lifestyle factors.Setting: prospective cohort analysis within the European Male Ageing Study.Participants: 2,816 community-dwelling men aged 40–79 years at baseline.Methods: Cox regression was used to examine the association of all-cause mortality with 25(OH)D, 1,25(OH)2D and PTH; cardiovascular and cancer mortality were modelled using competing-risks regression. Results were expressed as hazard ratios (HR) and 95% confidence intervals (CIs) for Cox models; sub-hazard ratios (SHR) and 95% CIs for competing-risks models.Results: a total of 187 men died during a median of 4.3 years of follow-up. Serum levels of 25(OH)D (per 1 SD decrease: HR = 1.45; 95% CI = 1.16, 1.81) and 1,25(OH)2D (per 1 SD decrease: HR = 1.20; 95% CI = 1.00, 1.44) were associated with an increased risk of all-cause mortality after adjusting for age, centre, smoking, self-reported morbidities, physical activity and functional performance. Only levels of 25(OH)D <25 nmol/l predicted cancer mortality (SHR = 3.33; 95% CI = 1.38, 8.04).Conclusion: lower 25(OH)D and 1,25(OH)2D levels independently predicted all-cause mortality in middle-aged and older European men. Associations with cancer mortality were only observed among men with very low levels of 25(OH)D. These associations were only partially explained by the range of adverse health and lifestyle factors measured here. [ABSTRACT FROM AUTHOR]

Background: vitamin D deficiency has been associated with an increased risk of mortality, but whether this relationship is causal or linked to co-existent comorbidity and adverse life factors remains uncertain. Our objective was to determine whether endogenous 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D) and parathyroid hormone (PTH) levels predicted all-cause, cardiovascular and cancer mortality independently of health and lifestyle factors.Setting: prospective cohort analysis within the European Male Ageing Study.Participants: 2,816 community-dwelling men aged 40–79 years at baseline.Methods: Cox regression was used to examine the association of all-cause mortality with 25(OH)D, 1,25(OH)2D and PTH; cardiovascular and cancer mortality were modelled using competing-risks regression. Results were expressed as hazard ratios (HR) and 95% confidence intervals (CIs) for Cox models; sub-hazard ratios (SHR) and 95% CIs for competing-risks models.Results: a total of 187 men died during a median of 4.3 years of follow-up. Serum levels of 25(OH)D (per 1 SD decrease: HR = 1.45; 95% CI = 1.16, 1.81) and 1,25(OH)2D (per 1 SD decrease: HR = 1.20; 95% CI = 1.00, 1.44) were associated with an increased risk of all-cause mortality after adjusting for age, centre, smoking, self-reported morbidities, physical activity and functional performance. Only levels of 25(OH)D <25 nmol/l predicted cancer mortality (SHR = 3.33; 95% CI = 1.38, 8.04).Conclusion: lower 25(OH)D and 1,25(OH)2D levels independently predicted all-cause mortality in middle-aged and older European men. Associations with cancer mortality were only observed among men with very low levels of 25(OH)D. These associations were only partially explained by the range of adverse health and lifestyle factors measured here. [ABSTRACT FROM AUTHOR]

Introduction: Spermatogenesis is a highly complex process involving several thousand genes, only a minority of which have been studied in infertile men. In a previous study, we identified a number of Copy Number Variants (CNVs) by high-resolution array-Comparative Genomic Hybridization (a-CGH) analysis of the X chromosome, including 16 patient-specific X chromosome-linked gains. Of these, five gains (DUP1A, DUP5, DUP20, DUP26 and DUP40) were selected for further analysis to evaluate their clinical significance. Materials and Methods: The copy number state of the five selected loci was analyzed by quantitative-PCR on a total of 276 idiopathic infertile patients and 327 controls in a conventional case-control setting (199 subjects belonged to the previous a-CGH study). For one interesting locus (intersecting DUP1A) additional 338 subjects were analyzed. Results and Discussion: All gains were confirmed as patient-specific and the difference in duplication load between patients and controls is significant (p = 1.65×10−4). Two of the CNVs are private variants, whereas 3 are found recurrently in patients and none of the controls. These CNVs include, or are in close proximity to, genes with testis-specific expression. DUP1A, mapping to the PAR1, is found at the highest frequency (1.4%) that was significantly different from controls (0%) (p = 0.047 after Bonferroni correction). Two mechanisms are proposed by which DUP1A may cause spermatogenic failure: i) by affecting the correct regulation of a gene with potential role in spermatogenesis; ii) by disturbing recombination between PAR1 regions during meiosis. This study allowed the identification of novel spermatogenesis candidate genes linked to the 5 CNVs and the discovery of the first recurrent, X-linked gain with potential clinical relevance. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Does CatSper have a role in the achievement of human sperm motility and in the Progesterone (P)-induced acrosome reaction (AR)? SUMMARY ANSWER CatSper1 expression is associated with human sperm progressive motility and the P-induced AR; it may have a role in the pathogenesis of asthenozoospermia. WHAT IS KNOWN ALREADY Knockout mice for any of the Catsper family genes fail to acquire hyperactivated motility and are infertile. CatSper channels mediate P-induced Ca2+ influx in human sperm. The role of CatSper in human sperm hyperactivated/activated motility and in asthenospermia is less clear. A few men with CatSper mutations have been described but the phenotype regarding sperm motility has not been well established. STUDY DESIGN, SIZE, DURATION The effects of two Catsper inhibitors, NNC55-0396 (NNC, 10 and 20 µM) and Mibefradil (Mib, 30 and 40 µM), were tested on human sperm motility parameters and the P-induced AR. Catsper1 protein expression was evaluated in unselected and swim-up selected sperm samples and in sperm from normo- and astheno-zoospermic subjects. PARTICIPANTS/MATERIALS, SETTING, METHODS Semen sample kinematic parameters were analysed by a CASA system. A fluorescent-labelled lectin was used to evaluate P-induced AR in live sperm by fluorescence microscopy. CatSper1 protein expression was determined by western blot analysis and by flow cytometry. Intracellular calcium concentrations ([Ca2+]i) were evaluated by a spectrofluorimetric method following sperm loading with the calcium-sensitive probe fura 2/AM. MAIN RESULTS AND THE ROLE OF CHANCE CatSper1 protein was localized in the tail of human sperm. CatSperI expression was higher in swim up selected than unselected sperm both when measured by western blot or by flow cytometry (52.7 ± 15.8% versus 27.2 ± 9.01%, n = 7, P < 0.01). Basal and P-stimulated [Ca2+]i were significantly higher in swim-up selected compared with unselected sperm. CatSper1 expression (western blot analysis) was found to be decreased in sperm from asthenozoospermic (n = 10) compared with those from normozoospermic (n = 9) men (intensity values relative to β-actin: 244.4 ± 69.3 versus 385.8 ± 139.5, P < 0.01). A positive correlation was found between CatSper1 protein expression and the percentage of sperm with progressive motility (n = 19, r = 0.59, P = 0.007). NNC (10 µM) and Mib (30 µM) significantly reduced the percentage of sperm with progressive motility and several kinematic parameters but did not affect the percentage of hyperactivated sperm. Their effects were the same whether they were added to swim-up selected and capacitated sperm or were added to the swim-up medium. Mib was found to have a slight but significant effect on sperm viability at both concentrations tested. P-stimulated AR was significantly reduced by both inhibitors (P < 0.05). Overall, our results indicate that, in human sperm, CatSper channel expression and function are associated with progressive motility and may be involved in the pathogenesis of asthenozoospermia. LIMITATIONS, REASONS FOR CAUTION In general, studies evaluating the effect of inhibitors have the limitation of the specificity of the molecules. We show here that Mib may have toxic effect on human sperm. Although most of the parameters have been evaluated in live sperm, the toxic effect could have contributed to the observed decreases. More studies are necessary to evaluate further the role of CatSper1 in asthenozoospermia. WIDER IMPLICATIONS OF THE FINDINGS In view of the involvement in P-induced AR and of the evidence of a role in the pathogenesis of astenozoospermia, CatSper channels may represent a promising target for the development of new drugs for the treatment of male infertility and for non-hormonal contraception. STUDY ... [ABSTRACT FROM AUTHOR]

Introduction We previously reported that in male patients consulting for sexual dysfunction, low prolactin ( PRL) levels were associated with metabolic syndrome ( MetS), arteriogenic erectile dysfunction, and incident major cardiovascular events. Aim The aim of this study is to assess the clinical associations of PRL levels in the European Male Ageing Study ( EMAS). Methods EMAS is a prospective, observational cohort of community-dwelling men aged 40-79 years old (mean age 60 ± 11 years old). PRL was available for 2,948 men. Main Outcome Measures Different parameters were evaluated including the Short Form-36 questionnaire, Becks Depression Inventory, the Adverse Life Events Scale, the Physical Activity Scale for the Elderly, and the EMAS sexual function questionnaire ( EMAS-SFQ). Results After the adjustment for confounders, PRL levels were inversely related with worsening of sexual function as compared with the previous year, as derived from change in sexual functioning domain of the EMAS-SFQ (adj. r = −0.043; P = 0.029). The strongest correlation ( Wald = 6.840; P = 0.009) was observed between lower PRL levels and reduced enjoyment of orgasmic experiences. Furthermore, an inverse relationship between PRL levels and stressful life events or depressive symptoms was observed. Low PRL was also negatively associated with an unhealthy metabolic phenotype as well as with the MetS (Wald = 5.229; P = 0.022). In line with these data, low PRL was associated with a lower level of physical activity and feeling unhealthier. Conclusions Low PRL is related to several metabolic, psychological, and sexual unhealthy characteristics in European men. Checking PRL might be useful to stratify men for cardiovascular risk and to encourage appropriate lifestyle changes. Corona G, Wu FC, Rastrelli G, Lee DM, Forti G, O'Connor DB, O'Neill TW, Pendleton N, Bartfai G, Boonen S, Casanueva FF, Finn JD, Huhtaniemi IT, Kula K, Punab M, Vanderschueren D, Rutter MK, Maggi M, and the EMAS Study Group. Low prolactin is associated with sexual dysfunction and psychological or metabolic disturbances in middle aged and elderly men: The European Male Aging Study (EMAS). J Sex Med 2014;11:240-253. [ABSTRACT FROM AUTHOR]

Background: Hyponatremia is the most common electrolyte disorder in clinical practice, and evidence to date indicates that severe hyponatremia is associated with increased morbidity and mortality. The aim of our study was to perform a meta-analysis that included the published studies that compared mortality rates in subjects with or without hyponatremia of any degree. Methods and Findings: An extensive Medline, Embase and Cochrane search was performed to retrieve the studies published up to October 1st 2012, using the following words: “hyponatremia” and “mortality”. Eighty-one studies satisfied inclusion criteria encompassing a total of 850222 patients, of whom 17.4% were hyponatremic. The identification of relevant abstracts, the selection of studies and the subsequent data extraction were performed independently by two of the authors, and conflicts resolved by a third investigator. Across all 81 studies, hyponatremia was significantly associated with an increased risk of overall mortality (RR = 2.60[2.31–2.93]). Hyponatremia was also associated with an increased risk of mortality in patients with myocardial infarction (RR = 2.83[2.23–3.58]), heart failure (RR = 2.47[2.09–2.92]), cirrhosis (RR = 3.34[1.91–5.83]), pulmonary infections (RR = 2.49[1.44–4.30]), mixed diseases (RR = 2.59[1.97–3.40]), and in hospitalized patients (RR = 2.48[2.09–2.95]). A mean difference of serum [Na+] of 4.8 mmol/L was found in subjects who died compared to survivors (130.1±5.6 vs 134.9±5.1 mmol/L). A meta-regression analysis showed that the hyponatremia-related risk of overall mortality was inversely correlated with serum [Na+]. This association was confirmed in a multiple regression model after adjusting for age, gender, and diabetes mellitus as an associated morbidity. Conclusions: This meta-analysis shows for the first time that even a moderate serum [Na+] decrease is associated with an increased risk of mortality in commonly observed clinical conditions across large numbers of patients. [ABSTRACT FROM AUTHOR]

Abstract: Few studies have directly compared the ability of the most commonly used models of frailty to predict mortality among community-dwelling individuals. Here, we used a frailty index (FI), frailty phenotype (FP), and FRAIL scale (FS) to predict mortality in the EMAS. Participants were aged 40–79 years (n =2929) at baseline and 6.6% (n =193) died over a median 4.3 years of follow-up. The FI was generated from 39 deficits, including self-reported health, morbidities, functional performance and psychological assessments. The FP and FS consisted of five phenotypic criteria and both categorized individuals as robust when they had 0 criteria, prefrail as 1–2 criteria and frail as 3+ criteria. The mean FI increased linearly with age (r 2 =0.21) and in Cox regression models adjusted for age, center, smoking and partner status the hazard ratio (HR) for death for each unit increase of the FI was 1.49. Men who were prefrail or frail by either the FP or FS definitions, had a significantly increased risk of death compared to their robust counterparts. Compared to robust men, those who were FP frail at baseline had a HR for death of 3.84, while those who were FS frail had a HR of 3.87. All three frailty models significantly predicted future mortality among community-dwelling, middle-aged and older European men after adjusting for potential confounders. Our data suggest that the choice of frailty model may not be of paramount importance when predicting future risk of death, enabling flexibility in the approach used. [Copyright &y& Elsevier]

Introduction The relationship between serum prostate-specific antigen ( PSA) and testosterone ( T) levels is still controversial. According to the 'saturation hypothesis,' a significant relationship is apparent only in the low T range. Aim To verify whether, in a large sample of male subjects seeking medical care for sexual dysfunction ( SD), PSA might represent a reliable marker of T levels. Methods A consecutive series of 3,156 patients attending our unit for SD was studied. Among them, only subjects without history of prostate disease and with PSA levels <4 ng/ mL (N = 2,967) were analyzed. Main Outcome Measures Several hormonal and biochemical parameters were studied, along with structured interview on erectile dysfunction ( SIEDY), ANDROTEST, and PsychoANDROTEST. Results Receiver operating characteristic curve analysis for predicting severe hypogonadism ( T < 8 nmol/ L) showed an accuracy of PSA = 0.612 ± 0.022 ( P < 0.0001), with the best sensitivity and specificity at PSA < 0.65 ng/ mL (65.2% and 55.5%, respectively). In the entire cohort, 254 subjects (8.6%) showed T < 8 nmol/ L and, among them, more than half (N = 141, 4.8%) had PSA < 0.65 ng/ mL. After adjusting for age, low PSA was associated with hypogonadism-related features (i.e., delayed puberty, lower testis volume) and associated conditions, such as metabolic syndrome (hazard ratio [ HR] = 1.506 [1.241-1.827]; P < 0.0001), type 2 diabetes ( HR = 2.044 [1.675-2.494]; P < 0.0001), and cardiovascular diseases ( HR = 1.275 [1.006-1.617]; P = 0.045). Furthermore, low PSA was associated with impaired sex- and sleep-related erections. The association between low PSA and hypogonadal symptoms and signs as well as with metabolic syndrome was retained even after adjusting for T levels. Sensitivity and positive predictive values of low PSA increased, whereas specificity and negative predictive value decreased as a function of age. Conclusions PSA is a marker of T concentrations and it may represent a new tool in confirming hypogonadism. The determination of PSA levels might give insights not only on the circulating levels of total T but also on its active fractions. Rastrelli G, Corona G, Vignozzi L, Maseroli E, Silverii A, Monami M, Mannucci E, Forti G, and Maggi M. Serum PSA as a predictor of testosterone deficiency. J Sex Med 2013;10:2518-2528. [ABSTRACT FROM AUTHOR]

Background. There has been little research on how late-life frailty interrelates with sexual health. Our objective was to examine the association of frailty with sexual functioning and satisfaction among older men. Methods. The study population consisted of 1,504 men aged 60 to 79 years, participating in the European Male Aging Study. Self-report questionnaires measured overall sexual functioning, sexual function–related distress, and erectile dysfunction. Frailty status was defined using a phenotype (FP) or index (FI). Associations between frailty and sexual function were explored using regression models. Results. Based on the frailty phenotype, 5% of men were classified as frail, and the mean frailty index was 0.18 (SD = 0.12). Frailty was associated with decreasing overall sexual functioning and increasing sexual function–related distress in multiple linear regressions adjusted for age, smoking, alcohol consumption, living arrangements, comorbidities, and depression. Frailty was also associated with an increased odds of erectile dysfunction after adjustment for the same confounders: odds ratio = 1.99 (95% confidence interval = 1.14, 3.48) and 4.08 (95% confidence interval = 2.63, 6.36) for frailty phenotype and frailty index, respectively. Conclusions. Frailty was associated with impaired overall sexual functioning, sexual function–related distress, and erectile dysfunction. Individuals assessed for frailty-related deficits may also benefit from an appraisal of sexual health as an important aspect of well-being and quality of life. [ABSTRACT FROM PUBLISHER]

Objective: To explore the Correlation models between body mass index (BMI) and sex hormones constructed from a mal cross-sectional survey and evaluate the effects of surgery-induced weight loss on sex hormones in morbidly obese subjects that are not predicted by the constructed BMI correlation models. Design: Cross-sectional population and longitudinal studies. Setting: Bariatric surgery center in a university hospital. Patient(s): A cross-sectional survey of a male general population of 161 patients (BMI median [interquartile range] = 29.2 [24.8-41.9] kg/m²) in addition to 24 morbidly obese subjects (BMI = 43.9 [40.8-53.8] kg/m²) who were undergoing bariatric surgery w prospectively studied for 6 and 12 months. Intervention(s): Bariatric surgery on 24 morbidly obese men. Main Outcome Measure(s): Cross-sectional population: construction of the best-fitting models describing the relationship between baseline BMI with total (Tr) and calculated free (cFT) testosterone, E2, sex hormone-binding globulin (SHBG), FSH, and LH levels Longitudinal study deviation between the observed sex hormone levels at 6- and 12-month follow-up and those expected on BMI bases. Result(s): The correlation of BMI with sex hormones was not univocally linear (E2), but the best-fitting model was exponential for TT, cFT, FSH, LH, and TT/E2 and power for SHBG. In addition to the significant improvement of all parameters observed after surgery in the longitudinal cohort, the increase in Tr and SHBG, but not in cFT, was significantly higher than expected from the corresponding weig loss at 6 months from surgery (14.80 [12.30-19.00] nM vs. 12.77 [10.92-13.64] rum and 40.0 [28.9-54.5] nM vs. 24.7 [22.5-25.8] n Tr and SHBG, respectively), remaining rather stable at 12 months. Conclusion(s): The increase in Tr and SHBG, but not the increase in cFT, after bariatric surge is greater than expected based on weight loss. [ABSTRACT FROM AUTHOR]

Objective: Few randomized clinical studies have evaluated the impact of diet and physical activity on testosterone levels in obese men with conflicting results. Conversely, studies on bariatric surgery in men generally have shown an increase in testosterone levels. The aim of this study is to perform a systematic review and meta-analysis of available trials on the effect of body weight loss on sex hormones levels. Design: Meta-analysis. Methods: An extensive Medline search was performed including the following words: 'testosterone', 'diet', 'weight loss', 'bariatric surgery', and 'males'. The search was restricted to data from January 1, 1969 up to August 31, 2012. Results: Out of 266 retrieved articles, 24 were included in the study. Of the latter, 22 evaluated the effect of diet or bariatric surgery, whereas two compared diet and bariatric surgery . Overall, both a low-calorie diet and bariatric surgery are associated with a significant (P < 0.0001) increase in plasma sex hormone-binding globulin-bound and -unbound testosterone levels (total testosterone (TT)), with bariatric surgery being more effective in comparison with the low-calorie diet (TT increase: 8.73 (6.51-10.95) vs 2.87 (1.68-4.07) for bariatric surgery and the low-calorie diet, respectively; both P < 0.0001 vs baseline). Androgen rise is greater in those patients who lose more weight as well as in younger, non-diabetic subjects with a greater degree of obesity . Body weight loss is also associated with a decrease in estradiol and an increase in gonadotropins levels. Multiple regression analysis shows that the degree of body weight loss is the best determinant of TT rise (B = 2.50 ± 0.98, P = 0.029). Conclusions: These data show that weight loss is associated with an increase in both bound and unbound testosterone levels. The normalization of sex hormones induced by body weight loss is a possible mechanism contributing to the beneficial effects of surgery in morbid obesity. [ABSTRACT FROM AUTHOR]

Background: the link between the vitamin D endocrine axis and frailty remains undefined, with few studies examining the joint effect of vitamin D and parathyroid hormone (PTH) levels. Our objective was to determine the association of frailty with serum 25-hydroxyvitamin D (25(OH)D) and PTH.Setting: cross-sectional analysis within the European Male Ageing Study (EMAS).Participants: a total of 1,504 community-dwelling men aged 60–79 years.Methods: frailty was classified using a frailty phenotype (FP) and frailty index (FI). The association of frailty with 25(OH)D and PTH was examined using multinomial logistic regression; individual FP criteria with 25(OH)D and PTH using binary logistic regression. Results were expressed as relative odds ratios (ROR) and 95% confidence intervals (CIs) for multinomial; odds ratios (OR) and 95% CIs for binary models.Results: using the FP, 5.0% of subjects were classified as frail and 36.6% as prefrail. Lower levels of 25(OH)D were associated with being prefrail (per 1 SD decrease: ROR = 1.45; 95% CI: 1.26–1.67) and frail (ROR = 1.89; 95% CI: 1.30–2.76), after adjusting for age, centre and health and lifestyle confounders (robust group = base category). Higher levels of PTH were associated with being frail after adjustment for confounders (per 1 SD increase: ROR = 1.24; 95% CI: 1.01–1.52). Comparable results were found using the FI. Among the five FP criteria only sarcopenia was not associated with 25(OH)D levels, while only weakness was associated with PTH.Conclusion: lower 25(OH)D and higher PTH levels were positively associated with frailty in older men. Prospective data would enable the temporal nature of this relationship to be explored further. [ABSTRACT FROM PUBLISHER]

The European Male Ageing Study (EMAS) was designed to examine the hypothesis that inter-individual and regional variability in symptomatic dysfunctions, alterations in body composition and health outcomes in ageing men can be explained by different rates of decline in anabolic hormones, the most important of which being testosterone. Between 2003 and 2005, 3369 community-dwelling men, aged between 40 and 79 years, were recruited from population-based registers in eight European centres to participate in the baseline survey, with follow-up investigations performed a median of 4.3 years later. Largely, identical questionnaire instruments and clinical investigations were used in both phases to capture contemporaneous data on general health (including cardiovascular diseases and chronic conditions), physical and cognitive functioning, mental health, sexual function, quality of life, bone health, chronic pain, disease biomarkers, hormones (sex hormones and metabolic hormones) and genetic polymorphisms. EMAS actively encourages new collaborations, data sharing for validation studies and participation in genetic study consortia. Potential collaborators should contact the principal investigator (F.C.W.W.) in the first instance. [ABSTRACT FROM AUTHOR]

Introduction The Atherosclerosis Risk in Communities ( ARIC) algorithm is one of the most efficient instruments for the prediction of incident type 2 diabetes. Recently, it has been shown to predict another relevant cardiovascular ( CV) risk factor, such as chronic kidney disease. Aim To verify whether, in patients with erectile dysfunction ( ED), the use of ARIC diabetes risk score might improve the efficacy in predicting major CV events of other CV risk algorithms specifically developed for the assessment of CV risk. Methods A consecutive series of 2,437 men (mean age 52.5 ± 12.9 years) attending our outpatient clinic for sexual dysfunction was retrospectively studied. A subset of this sample ( N = 1,687) was enrolled in a longitudinal study (mean follow-up of 4.3 ± 2.6 years). Main Outcome Measures The assessment of metabolic risk was evaluated with the ARIC algorithm. The assessment of CV risk was evaluated using the Progetto Cuore risk engine. Results In the cross-sectional study, ARIC score was inversely related with testosterone levels, sexual functioning, and penile blood flow. When longitudinal sample was analyzed, higher baseline ARIC score significantly predicted major adverse cardiovascular event ( MACE) even when subjects with diabetes mellitus at baseline were excluded from the analysis (hazard ratio = 1.522 [1.086-2.135]; P = 0.015 for trend). In addition, among subjects classified as 'low risk' ( CV risk <20% at 10 years corresponding to <9% at 4.3 years) by Progetto Cuore, a receiving operating curve ( ROC) analysis for ARIC (vs. MACE) allowed the identification of a threshold of 0.22, which had a positive predictive value for 4.3-year MACE of 9%. Applying the ARIC score (with a threshold of 0.22) to Progetto Cuore 'low-risk' subjects, we could classify as 'at high risk' 89.8% of subjects with incident MACE vs. 79.6% with Progetto Cuore only. Conclusions In patients with ED, identifying prediabetes, even with algorithms, predicts long-term CV events. [ABSTRACT FROM AUTHOR]

Introduction Hypoactive sexual desire is defined as a persistent or recurrent deficient or absent sexual fantasies or desire for sexual activity that should not be comorbid with other medical conditions or with the use of psychoactive medications. Reduced libido is a symptom referring more to a reduction in sexual drive for sexual activity. Aim To investigate the risk factors of primary reduced libido (i.e., not associated with conditions causing loss of libido such as hypogonadism, hyperprolactinemia, psychopathology, and/or psychoactive medications) or secondary reduced libido (i.e., with aforementioned conditions) in male patients with sexual dysfunction. Method A consecutive series of 3,714 men (mean age 53.2 ± 12.5 years) was retrospectively studied. Main Outcome Measures Patient's reduced libido was evaluated using question #14 of structured interview for erectile dysfunction ( SIEDY) ('Did you have more or less desire to make love in the last 3 months?'). Results Reduced libido was comorbid with erectile dysfunction, premature ejaculation, and delayed ejaculation in 38%, 28.2%, and 50%, respectively, whereas it was isolated in 5.1%. Reduced libido prevalence was substantially increased by hypogonadism, almost doubled by psychopathology and universally present in subjects with hyperprolactinemia (secondary reduced libido). Subjects with primary reduced libido are characterized by higher postschool qualification, more disturbances in domestic and dyadic relationships, and an overall healthy body (lower glycemia and triglyceride levels). Accordingly, in patients with primary reduced libido, the risk of major cardiovascular events as calculated with the Progetto Cuore algorithm was lower than in the rest of the sample. Features of hypogonadism- or psychopathology-associated reduced libido essentially reflect their underlying conditions. Comorbidity with other sexual dysfunctions did not affect the main characteristics of primary or secondary reduced libido. Conclusions Primary and secondary reduced libido have different risk factors and clinical characteristics. Recognizing primary or secondary reduced libido will help clinicians to identify comorbidities and to tailor appropriate treatments. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction. The relational domain of erectile dysfunction (ED) is difficult to investigate in a clinical setting. We developed and validated SIEDY, a 13-item structured interview, that evaluates, besides the organic (Scale 1) and intra-psychic (Scale 3) domains, also the relational one (Scale 2). We previously established a pathological threshold for SIEDY Scale 1 and 3. Aim. The aim of this study is to identify a pathological threshold of SIEDY Scale 2. Method. A nonselected, consecutive series of 2,992 subjects with ED was retrospectively evaluated. In a first consecutive series of 844 patients (Sample A, studied without systematically applying a psychometric test: Middlesex Hospital Questionnaire), a pathological threshold of SIEDY Scale 2 score was identified through receiver operating characteristic, using, as surrogate marker of impaired couple relationship, at least a positive answer to two standard questions on conflict within the couple and on the presence of extramarital affairs. Main Outcome Measure. Sensitivity and specificity, along with possible associations with biological and psychological correlates were verified in a further sample of 2,148 patients (Sample B). Results. In Sample A, a threshold of Scale 2 score ≥2 predicts couple impairment with a sensitivity of 53% and specificity of 66% and an overall accuracy of 62.0 ± 2.2% ( P < 0.0001). When this threshold was verified in sample B, Scale 2 score ≥2 was associated with a higher risk of anxiety and depressive symptoms, higher prevalence of psychopathology, and higher Scale 3 scoring, even after adjusting for confounders. In the same sample, a Scale 2 score ≥2 was associated with a reduced intimacy during sexual intercourse and overall worse sexual functioning. Conclusions. Until now, no instrument is available to quantify the marital domain of ED. The validation of a threshold of SIEDY Scale 2 score (≥2) represents an easy tool for the identification of ED patients with a relevant marital impairment. Boddi V, Corona G, Fisher AD, Mannucci E, Ricca V, Sforza A, Forti G, and Maggi M. 'It takes two to tango': The relational domain in a cohort of subjects with erectile dysfunction (ED). J Sex Med 2012;9:3126-3136. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction. The frequency and the clinical characteristics of erectile dysfunction (ED) and premature ejaculation (PE) in infertile men have been poorly investigated. Aim. To assess the prevalence of ED and PE and their clinical correlates in men seeking medical care for couple infertility. Methods. A consecutive series of 244 men (mean age 35.2 ± 7.8) with couple infertility was systematically evaluated. Erectile function was investigated with the International Index of Erectile Function-15 erectile function domain (IIEF-15-EFD) whereas ejaculatory status with the PE diagnostic tool (PEDT). Main Outcome Measures. All patients underwent psychological (Middlesex Hospital Questionnaire [MHQ]), prostatitis symptoms (National Institutes of Health-chronic prostatitis symptom index [NIH-CPSI]); hormonal, seminal, and interleukin 8 (sIL-8; a surrogate marker of prostatitis) evaluation; along with scrotal and transrectal color Doppler ultrasound (CDU) assessment. Results. ED was found in 43 (17.8%) and PE in 38 (15.6%) subjects. After adjusting for age, IIEF-15-EFD score was negatively associated with depressive symptoms (MHQ-D score), somatization (MHQ-S score), NIH-CPSI total, and quality of life subdomain score. In a logistic multivariate model, among all these variables, only depression was significantly associated with ED (adjusted odds ratio [OR] = 1.19 [1.02-1.39]; P < 0.05). PEDT score was positively associated with prostatitis symptoms and signs, such as sIL-8 and prostate CDU abnormalities (including arterial prostatic peak systolic velocity, APPSV), phobic anxiety (MHQ-P score), and calculated free testosterone (cFT). The association between PE and NIH-CPSI score or APPSV was confirmed even after adjustment for age, MHQ-P score and cFT (adjusted OR = 1.11 [1.05-1.17]; P < 0.0001 and 1.22 [1.03-1.44]; P = 0.02, for NIH-CPSI score and APPSV, respectively). Conclusions. ED and PE are reported by one in six infertile patients. ED is mainly associated with depressive symptoms, while PEDT score is positively associated with prostatitis symptoms and signs, phobic anxiety, and cFT. Lotti F, Corona G, Rastrelli G, Forti G, Jannini EA, and Maggi M. Clinical correlates of erectile dysfunction and premature ejaculation in men with couple infertility. J Sex Med **;**:**-**. [ABSTRACT FROM AUTHOR]

Context: The role of CNVs in male infertility is poorly defined, and only those linked to the Y chromosome have been the object of extensive research. Although it has been predicted that the X chromosome is also enriched in spermatogenesis genes, no clinically relevant gene mutations have been identified so far. Objectives: In order to advance our understanding of the role of X-linked genetic factors in male infertility, we applied high resolution X chromosome specific array-CGH in 199 men with different sperm count followed by the analysis of selected, patient-specific deletions in large groups of cases and normozoospermic controls. Results: We identified 73 CNVs, among which 55 are novel, providing the largest collection of X-linked CNVs in relation to spermatogenesis. We found 12 patient-specific deletions with potential clinical implication. Cancer Testis Antigen gene family members were the most frequently affected genes, and represent new genetic targets in relationship with altered spermatogenesis. One of the most relevant findings of our study is the significantly higher global burden of deletions in patients compared to controls due to an excessive rate of deletions/person (0.57 versus 0.21, respectively; p = 8.785x0-6) and to a higher mean sequence loss/person (11.79 Kb and 8.13 Kb, respectively; p = 3.435x10-4). Conclusions: By the analysis of the X chromosome at the highest resolution available to date, in a large group of subjects with known sperm count we observed a deletion burden in relation to spermatogenic impairment and the lack of highly recurrent deletions on the X chromosome. We identified a number of potentially important patient-specific CNVs and candidate spermatogenesis genes, which represent novel targets for future investigations. [ABSTRACT FROM AUTHOR]