Elisa Maseroli

Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis.

Introduction: Recent reports have significantly halted the enthusiasm regarding androgen-boosting; suggesting that testosterone supplementation (TS) increases cardiovascular (CV) events. Areas covered: In order to overcome some of the limitations of the current evidence, the authors performed an updated systematic review and meta-analysis of all placebo-controlled randomized clinical trials (RCTs) on the effect of TS on CV-related problems. Out of 2747 retrieved articles, 75 were analyzed, including 3016 and 2448 patients in TS and placebo groups, respectively, and a mean duration of 34 weeks. Our analyses, performed on the largest number of studies collected so far, indicate that TS is not related to any increase in CV risk, even when composite or single adverse events were considered. In RCTs performed in subjects with metabolic derangements a protective effect of TS on CV risk was observed. Expert opinion: The present systematic review and meta-analysis does not support a causal role between TS and adverse CV events. Our results are in agreement with a large body of literature from the last 20 years supporting TS of hypogonadal men as a valuable strategy in improving a patient’s metabolic profile, reducing body fat and increasing lean muscle mass, which would ultimately reduce the risk of heart disease.

THERAPY OF ENDOCRINE DISEASE: Testosterone supplementation and body composition: results from a meta-analysis study

OBJECTIVE The role of testosterone (T) in regulating body composition is conflicting. Thus, our goal is to meta-analyse the effects of T supplementation (TS) on body composition and metabolic outcomes. METHODS All randomized controlled trials (RCTs) comparing the effect of TS on different endpoints were considered. RESULTS Overall, 59 trials were included in the study enrolling 3029 and 2049 patients in TS and control groups respectively. TS was associated with any significant modification in body weight, waist circumference and BMI. Conversely, TS was associated with a significant reduction in fat and with an increase in lean mass as well as with a reduction of fasting glycaemia and insulin resistance. The effect on fasting glycaemia was even higher in younger individuals and in those with metabolic diseases. When only RCTs enrolling hypogonadal (total T <12  mol/l) subjects were considered, a reduction of total cholesterol as well as triglyceride (TGs) levels were also detected. Conversely, an improvement in HDL cholesterol levels as well as in both systolic and diastolic blood pressure was not observed. CONCLUSION Our data suggest that TS is able to improve body composition and glycometabolic profile particularly in younger subjects and in those with metabolic disturbances. Specifically designed studies are urgently needed to confirm this point.

Injectable testosterone undecanoate for the treatment of hypogonadism

Introduction: Injectable testosterone undecanoate (TU) is a long-acting testosterone (T) formulation available for the treatment of male hypogonadism (HG) since 2003. Areas covered: The efficacy and safety of injectable TU are assessed, as obtained by meta-analyzing available evidence. An extensive Medline, Embase and Cochrane search was performed. All uncontrolled and placebo-controlled randomized clinical trials (RCTs), evaluating the effect of injectable TU on different outcomes, were included. Of the 98 retrieved articles, 33 were included in the study. Among those, 11 were placebo-controlled RCTs. Injectable TU was significantly associated with a reduction of fat mass and HbA1c in both controlled and uncontrolled trials, in particular when hypogonadal subjects were enrolled. Similar results were observed for the improvement of erectile function. In addition, TU ameliorated several other outcomes, including blood pressure, lipid profile, waist circumference and body mass index in uncontrolled studies, but these data were not confirmed in placebo-controlled trials. The treatment was well tolerated and no risk of prostate cancer or cardiovascular disease was observed. Expert opinion: Injectable TU is a safe and effective treatment for male HG. The possibility of a therapeutic intervention just four to five times per year frees the patient, at least partially, from having a chronic condition, thus maintaining a positive, active role in self-caring.

Prevalence of Endocrine and Metabolic Disorders in Subjects with Erectile Dysfunction: A Comparative Study

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.

Metabolic syndrome and prostate abnormalities in male subjects of infertile couples.

No previous study has evaluated systematically the relationship between metabolic syndrome (MetS) and prostate-related symptoms and signs in young infertile men. We studied 171 (36.5 ± 8.3-years-old) males of infertile couples. MetS was defined based on the National Cholesterol Education Program Third Adult Treatment Panel. All men underwent hormonal (including total testosterone (TT) and insulin), seminal (including interleukin-8 (IL-8), seminal plasma IL-8 (sIL-8)), scrotal and transrectal ultrasound evaluations. Because we have previously assessed correlations between MetS and scrotal parameters in a larger cohort of infertile men, here, we focused on transrectal features. Prostate-related symptoms were assessed using the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) and the International Prostate Symptom Score (IPSS). Twenty-two subjects fulfilled MetS criteria. In an age-adjusted logistic ordinal model, insulin levels increased as a function of MetS components (Wald = 29.5, P < 0.0001) and showed an inverse correlation with TT (adjusted r = -0.359, P< 0.0001). No association between MetS and NIH-CPSI or IPSS scores was observed. In an age-, TT-, insulin-adjusted logistic ordinal model, an increase in number of MetS components correlated negatively with normal sperm morphology (Wald = 5.59, P< 0.02) and positively with sIL-8 levels (Wald = 4.32, P < 0.05), which is a marker of prostate inflammation, with prostate total and transitional zone volume assessed using ultrasound (Wald = 17.6 and 12.5, both P < 0.0001), with arterial peak systolic velocity (Wald = 9.57, P = 0.002), with texture nonhomogeneity (hazard ratio (HR) = 1.87 (1.05–3.33), P < 0.05), with calcification size (Wald = 3.11, P < 0.05), but not with parameters of seminal vesicle size or function. In conclusion, in males of infertile couples, MetS is positively associated with prostate enlargement, biochemical (sIL8) and ultrasound-derived signs of prostate inflammation but not with prostate-related symptoms, which suggests that MetS is a trigger for a subclinical, early-onset form of benign prostatic hyperplasia.

Low testosterone syndrome protects subjects with high cardiovascular risk burden from major adverse cardiovascular events.

The role of testosterone (T) in the cardiovascular (CV) health of men is controversial. Some data suggest that hypogonadism is associated with CV mortality but not morbidity, however, recent evidence shows that hypogonadal subjects treated with T replacement therapy have a higher incidence of new CV events. The aim of this study is to analyse whether gonadal status might predict new CV event incidence according to a patients previous history of CV events, in a cohort of subjects complaining of sexual dysfunction. A consecutive series of 1687 patients was followed‐up for a mean time of 4.3 ± 2.6 years for new occurrence of CV events, detecting 139 events. Hypogonadism (total T < 12 nmol/L) was not associated with an increased incidence of new CV events in the entire cohort. However, when considering patients with a previous history of CV events, hypogonadism was associated with a reduced risk of new CV events, even after adjusting for confounders (hazard ratios – HR = 0.498 [0.240; 0.996]; p = 0.049), whereas no relationship was observed in subjects free of previous CV events. Similar results were observed when reduced testis volume (TV) was considered as a predictor of new CV events in subjects with previous CV events (HR = 0.486 [0.257; 0.920]; p = 0.027). In patients with a history of previous CV events, but not in those without previous CV events, having both low T and low TV was associated with a lower incidence of new CV events as compared with subjects with only one or none of these conditions, even after adjusting for confounders (HR = 0.514 [0.306; 0.864]; p for trend < 0.02). Notably, CV risk estimated with risk engines based on traditional risk factors was not different between hypogonadal and eugonadal subjects. In conclusion, hypogonadism could be interpreted as a protective mechanism in unhealthy conditions, such as previous CV events, to avoid fatherhood and spare energy.

Frequency of sexual activity and cardiovascular risk in subjects with erectile dysfunction: cross-sectional and longitudinal analyses

Erectile dysfunction (ED) is risk factor for cardiovascular (CV) events. The relationship between sexual activity and incident major adverse cardiovascular events (MACE) in subjects at high CV risk is conflicting and never investigated in ED subjects. The aim of this study was to investigate relationships between frequency of sexual attempts and incident MACE and to retrospectively explore its main determinants in subjects with sexual dysfunction. A consecutive series of 2187 subjects (mean age 49.9 ± 11.6 years old) attending the Outpatient Clinic for sexual dysfunction was retrospectively studied. A subset of the previous sample (N = 1687) was enrolled in a longitudinal study. Frequency of sexual intercourse (coital and non‐coital) was assessed using a standard question (‘During the last 3 months how many sexual attempts per month did you have?’). In the whole sample, sexual attempts were an age‐ and testosterone‐dependent phenomenon, while no association between frequency of sexual intercourse and ED or premature and delayed ejaculation, was observed. However, when the same analysis was performed according to age tertiles (I = 17–46, II = 47–59, III = 60–88 years old), ED was significantly associated with a higher risk of reduced sexual intercourse in younger (hazard ratio = 1.857 [1.066–3.234]; p = 0.029), but not in middle‐aged or older individuals. The marital component, as assessed by SIEDY Scale 2, played a major role in regulating sexual frequency in all age bands. Depressive symptoms represent another independent risk factor for reduced sexual activity (adj r = −0.139; p < 0.0001), in an age‐dependent manner. When longitudinal data were analysed, a higher frequency of sexual intercourse significantly reduced the risk of MACE even after adjusting for known CV risk factors for this cohort. Identifying among mild‐to‐moderate ED subjects those with lower frequency of sexual activity might provide an opportunity to modify their behaviour and to discover subthreshold comorbidities, possibly preventing forthcoming CV events.

Current smoking is associated with lower seminal vesicles and ejaculate volume, despite higher testosterone levels, in male subjects of infertile couples

STUDY QUESTION What is the impact of smoking behaviour on seminal, hormonal and male genital tract ultrasound parameters in subjects seeking medical care for couple infertility? STUDY ANSWER In males of infertile couples, current smokers (CS), when compared with non-smokers, show lower ejaculate and ultrasound-derived seminal vesicles (SV) volume, despite higher testosterone levels. WHAT IS KNOWN ALREADY Data on the effects of smoking on male fertility are conflicting. A correlation between smoking and reduced semen parameters has been reported, however, with a high heterogeneity among studies. An association between smoking behaviour and higher testosterone levels in men has been described in several, but not all, the previous studies. No study has systematically evaluated the impact of smoking on the male genital tract ultrasound characteristics. STUDY DESIGN, SIZE AND DURATION Retrospective cross-sectional analysis of a consecutive series of 426 subjects seeking medical care for couple infertility from January 2010 to July 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS From the entire cohort, 394 men (age 36.0 ± 8.0 years) free of genetic abnormalities were selected. All subjects underwent a complete andrological and physical examination, biochemical and hormonal assessment, scrotal and transrectal colour-Doppler ultrasound and semen analysis (including seminal interleukin-8 levels, sIL-8) within the same day. MAIN RESULTS AND THE ROLE OF CHANCE Among the patients evaluated, 229 were never smokers (NS), 56 past smokers (PS) and 109 CS. When CS were compared with the rest of the sample (non-smokers, NS + PS), in a multivariate model (analysis of covariance, ANCOVA) adjusted for age, lifestyle (including alcohol, cannabis and physical activity), BMI and sex hormone-binding globulin, significantly higher androgen (total testosterone, P = 0.001; calculated free testosterone, P < 0.005) and lower FSH (P < 0.05) levels were observed in CS. However, when total testosterone was also included in the multivariate model as a further covariate, the difference in FSH levels was not confirmed. In a similar model, a lower ejaculate volume (P < 0.01) and a higher prevalence of normal sperm morphology (P < 0.02) were also detected in CS in comparison with the rest of the sample. However, when total testosterone was also included in the multivariate model as a further covariate, only the difference in ejaculate volume between CS and non-smokers was confirmed (-0.61 ± 0.23 ml, P < 0.01). Finally, CS showed lower total SV volume, before and after ejaculation, even after adjusting for confounders (P = 0.02 and <0.01, respectively). Similar results were observed when the reported number of cigarettes smoked or the number of pack-years was considered separately. LIMITATIONS, REASONS FOR CAUTION The present results are derived from patients consulting an Andrology Clinic for couple infertility, who could have different characteristics from the general male population or males consulting general practitioners for reasons other than couple infertility. In addition, we did not have a true control group composed of age-matched, apparently healthy, fertile men, and therefore true normative data of sonographic parameters cannot be inferred. Due to the cross-sectional nature of our study, neither a causality hypothesis nor mechanistic models can be drawn. Finally, this is a retrospective study, and further prospective studies are required. WIDER IMPLICATIONS OF THE FINDINGS We report an apparent paradox in CS: lower SV volume despite higher testosterone levels. Our data suggest that smoking may negatively affect SV volume in an independent manner, as the difference between CS and non-smokers retained significance after adjusting for confounders including testosterone. This is the first study reporting such ultrasound evidence. How this new smoking-related alteration, along with low semen volume, impacts male fertility needs to be addressed by further studies. STUDY FUNDING/COMPETING INTERESTS No funding was received for the study. None of the authors have any conflict of interest to declare.

Characteristics of compensated hypogonadism in patients with sexual dysfunction.

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.

Testosterone Replacement Therapy and Cardiovascular Risk: A Review

Recent reports in the scientific and lay press have suggested that testosterone (T) replacement therapy (TRT) is likely to increase cardiovascular (CV) risk. In a final report released in 2015, the Food and Drug Administration (FDA) cautioned that prescribing T products is approved only for men who have low T levels due to primary or secondary hypogonadism resulting from problems within the testis, pituitary, or hypothalamus (e.g., genetic problems or damage from surgery, chemotherapy, or infection). In this report, the FDA emphasized that the benefits and safety of T medications have not been established for the treatment of low T levels due to aging, even if a mans symptoms seem to be related to low T. In this paper, we reviewed the available evidence on the association between TRT and CV risk. In particular, data from randomized controlled studies and information derived from observational and pharmacoepidemiological investigations were scrutinized. The data meta-analyzed here do not support any causal role between TRT and adverse CV events. This is especially true when hypogonadism is properly diagnosed and replacement therapy is correctly performed. Elevated hematocrit represents the most common adverse event related to TRT. Hence, it is important to monitor hematocrit at regular intervals in T-treated subjects in order to avoid potentially serious adverse events.