Giulia Rastrelli

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.

Testosterone, cardiovascular disease and the metabolic syndrome

Recent evidence suggests that low, rather than high, testosterone (T) is associated with increased male morbidity and mortality. We reviewed relationships between hypogonadism, metabolic syndrome (MetS) and cardiovascular (CV) disease (CVD), along with erectile dysfunction (ED), a common condition in the three diseases. Although several experimental data indicate that T exerts a protective effect on vascular function, epidemiological studies do not support a link between hypogonadism and CVD and three meta-analyses found no significant effect of testosterone replacement therapy (TRT) on CV events. Low T is associated with increased risk of CV death in community-dwelling men, and in men with ED. It is possible that both low T and CVD are associated with another, still unknown (or not assessed) factor, thus explaining the association, in the absence of any causal relationship. A meta-analysis on the effect of TRT in MetS-associated hypogonadism demonstrated positive effects of T on some of the components of MetS. Large-scale interventional studies with TRT are therefore advisable.

Hypogonadism and metabolic syndrome

Background: The relationship between metabolic syndrome (MetS), male hypogonadism and their possible interaction in cardiovascular (CV) risk stratification are not completely understood. Aim: We reviewed relationships between testosterone (T) and MetS emphasizing their possible interaction in the pathogenesis of CV diseases. Materials and methods: A systematic search of published evidence was performed using Medline (1969 to January 2011). Results: Cross-sectional data have shown that subjects with MetS have lower levels of total T (TT) (about 3 nmol/l), as hypogonadism is more evident in subjects with than in those without erectile dysfunction (ED) than in those without. Longitudinal evidence shows that low T is allocated with a higher risk of subsequent development of MetS, although the reverse condition is also possible. Which are the factors in MetS responsible for the low T is not completely clarified. In clinical studies, increased waist circumference is the major determinant of MetS-associated hypogonadism. Our experiments in rabbits do not support the idea that visceral fat is the main determinant of MetS-associated male hypogonadism. Only few randomized clinical trials have evaluated the impact of T replacement therapy (TRT) in patients with MetS. Available evidence suggests that TRT decreases visceral fat accumulation and ameliorates insulin sensitivity, whereas androgen deprivation increases abdominal adiposity. Conclusions: The clinical significance of the MetS-associated hypogonadism needs further clarifications. In particular, it has not been completely clarified if low T might be considered a cause or a consequence of MetS. The benefit of TRT in term of the reduction of CV risk needs to be confirmed in larger and longer studies.

ORIGINAL RESEARCH–EPIDEMIOLOGY: Selective Serotonin Reuptake Inhibitor-Induced Sexual Dysfunction

INTRODUCTION Sexual dysfunctions are often present in subjects with mood disturbances; however. antidepressants can induce per se sexual dysfunctions. AIM To explore the relationship between the use of selective serotonin reuptake inhibitors (SSRIs), non-SSRIs antidepressants and benzodiazepines (BDZ), hormonal parameters, and reported sexual dysfunction (as assessed by the Structured Interview on Erectile Dysfunction [SIEDY]) in male subjects with comparable psychopathological symptoms (as assessed by the Middlesex Hospital Questionnaire [MHQ] a self-reported test for the screening of mental disorders in a non-psychiatric setting). METHODS A consecutive series of 2,040 (mean age 51 +/- 13 years) male patients with sexual dysfunction was studied. MAIN OUTCOME MEASURES Several hormonal and biochemical parameters were investigated, along with SIEDY and the MHQ. RESULTS Higher prolactin was observed only in patients using SSRIs, whereas no other hormonal difference was found after adjustment for confounders. Use of SSRIs was associated with a twofold risk for patient hypoactive sexual desire and with a higher impairment of reported erectile function. However, no difference in penile blood flow was observed. A very high risk (sevenfold) for delayed ejaculation (DE) was observed in SSRI users. Interestingly, the association with the mild, but not severe, form of DE was observed also in subjects using non-SSRI antidepressants (3.35 [1.48-7.59]; P < 0.005). Different life stressors and relational parameters were also associated with SSRI use. SSRI users reported less enjoyment with masturbation and decreased partner desire and climax. Conversely, a lack of significant association was observed among BDZ or non-SSRI antidepressant users and all the aforementioned life-stressors and relational parameters. CONCLUSIONS SSRIs can negatively affect all the steps of the male sexual response cycle (desire-arousal-excitement-orgasm). SSRI-associated sexual dysfunction has a deleterious effect on both auto- and couple-erotic performances. Conversely, other antidepressants and BDZ are less often associated with sexual impairment.

Update in Testosterone Therapy for Men (CME)

INTRODUCTION 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. AIM To review the pathogenesis of male hypogonadism and the available preparations for TRT, along with the main clinical outcomes. METHODS 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. MAIN OUTCOME MEASURES 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. RESULTS 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. CONCLUSIONS 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.

Metabolic syndrome and lower urinary tract symptoms: the role of inflammation.

Background:Epidemiological data indicate that lower urinary tract symptoms (LUTS)/BPH can be associated with metabolic syndrome (MetS). Chronic inflammation has been proposed as a candidate mechanism at the crossroad between these two clinical entities.Aim of study is to examine the correlation among pre-operatory LUTS/BPH severity, MetS features and inflammatory infiltrates in prostatectomy specimens.Methods:A total of 271 consecutive men treated with simple prostatectomy were retrospectively selected for this study in two tertiary referral centers for LUTS/BPH. Prostate diameters and volume were measured by transrectal ultrasound, LUTS scored by International Prostate Symptom Score (IPSS) and obstruction by uroflowmetry. The International Diabetes Federation and American Heart Association and the National Heart, Lung and Blood Institute was used to define MetS. The inflammatory infiltrate was investigated combining anatomic location, grade and extent of flogosis into the overall inflammatory score (IS); the glandular disruption (GD) was used as a further marker.Results:Eighty-six (31.7%) men were affected by MetS. Prostatic volume and anterior-posterior (AP) diameter were positively associated to the number of MetS components. Among MetS determinants, only dyslipidaemia (increased serum triglycerides and reduced serum high-density lipoprotein) was associated with an increased risk of having a prostatic volume >60 cm3 (hazard ratio (HR)=3.268, P<0.001). A significant positive correlation between the presence of MetS and the IS was observed. MetS patients presented lower uroflowmetric parameters as compared with those without MetS (Maximum flow rate (Qmax): 8.6 vs 10.1, P=0.008 and average flow rate (Qave): 4.6 vs 5.3, P=0.033, respectively), and higher obstructive urinary symptoms score (P=0.064). A positive correlation among both IS–GD and IPSS Score was also observed (adjusted r=0.172, P=0.008 and adjusted r=0.128, P=0.050).Conclusions:MetS is associated with prostate volume, prostatic AP diameter and intraprostatic IS. The significantly positive association between MetS and prostatic AP diameter could support the observation that MetS patients presented lower uroflowmetric parameters. In conclusion, MetS can be regarded as a new determinant of prostate inflammation and BPH progression.

The hormonal control of ejaculation

Hormones regulate all aspects of male reproduction, from sperm production to sexual drive. Although emerging evidence from animal models and small clinical studies in humans clearly point to a role for several hormones in controlling the ejaculatory process, the exact endocrine mechanisms are unclear. Evidence shows that oxytocin is actively involved in regulating orgasm and ejaculation via peripheral, central and spinal mechanisms. Associations between delayed and premature ejaculation with hypothyroidism and hyperthyroidism, respectively, have also been extensively documented. Some models suggest that glucocorticoids are involved in the regulation of the ejaculatory reflex, but corresponding data from human studies are scant. Oestrogens regulate epididymal motility, whereas testosterone can affect the central and peripheral aspects of the ejaculatory process. Overall, the data of the endocrine system in regulating the ejaculatory reflex suggest that widely available endocrine therapies might be effective in treating sexual disorders in these men. Indeed, substantial evidence has documented that treatments of thyroid diseases are able to improve some ejaculatory difficulties.

How to recognize late-onset hypogonadism in men with sexual dysfunction

Late-onset hypogonadism (LOH) has been considered the most common form of male hypogonadism with a prevalence of approximately 1 in 100 men. Diagnosis of LOH should be made in symptomatic men with unequivocally low serum testosterone (T) levels. However, its clinical presentation is often insidious and difficult to recognize because it is characterized by nonspecific symptoms that make differential diagnosis with physiological ageing problematic. Sexual dysfunction is the most important determinant for medical consultation and the most specific symptom associated with low T. We therefore analysed a consecutive series of 1734 subjects who attended our unit for sexual dysfunction to investigate the associations between low T (different thresholds), sexual parameters, medical history data (delayed puberty, pituitary disease or cryptorchidism) and their physical exam results. Metabolic parameters, in particular waist circumference, display the greatest accuracy in detecting low T. We found that only the association of several symptoms and signs could significantly raise the clinical suspicion of low T. Structured inventories, which cluster together symptoms and signs of hypogonadism, can help clinicians suspect androgen deficiency. In particular, structured interviews, such as ANDROTEST, have been demonstrated to have a greater accuracy when compared to self reported questionnaires in detecting low T levels.

Benign prostatic hyperplasia: a new metabolic disease?

BackgroundBenign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) are conditions extremely prevalent in the aging male. Although androgens are involved in prostate growth during developmental age, their role in the pathogenesis of BPH/LUTS is debated. Recent data indicate that low testosterone and high estradiol favor disease progression. In addition, the role of other determinants, such as metabolic syndrome or prostate inflammation, is emerging.AimWe reviewed the evidence regarding the pathogenesis of BPH/LUTS with particular attention to metabolic influence.Materials and methodsA review of published evidence was performed using Medline.ResultsAvailable evidence shows that a three-hit hypothesis can be drawn. An overt, or even a subclinical, bacterial or viral infection could induce prostatic inflammation (first hit) that could be autosustained or exacerbated by the presence of an altered metabolism and in particular by hypercholesterolemia (second hit). Hypogonadism and/or hyperestrogenism could act as a third hit, favoring the maintenance of this inflammatory state. The combined action of all three hits, or even two of them, may result in overexpression of Toll-like receptors (TLRs), transformation of prostatic cells into antigen-presenting cells and activation of resident human prostate-associated lymphoid tissue ending in overproduction of growth factors which, in turn, will induce prostate remodeling and further prostate enlargement. The mechanical obstruction, along with the direct action of the unfavorable metabolic and hormonal milieu on the bladder neck, helps in generating LUTS.ConclusionInflammation, dyslipidemia and altered sex-steroid milieu mutually concur in determining BPH/LUTS.

ORIGINAL RESEARCHORIGINAL RESEARCH–EPIDEMIOLOGY: Selective Serotonin Reuptake Inhibitor-Induced Sexual Dysfunction

INTRODUCTION Sexual dysfunctions are often present in subjects with mood disturbances; however. antidepressants can induce per se sexual dysfunctions. AIM To explore the relationship between the use of selective serotonin reuptake inhibitors (SSRIs), non-SSRIs antidepressants and benzodiazepines (BDZ), hormonal parameters, and reported sexual dysfunction (as assessed by the Structured Interview on Erectile Dysfunction [SIEDY]) in male subjects with comparable psychopathological symptoms (as assessed by the Middlesex Hospital Questionnaire [MHQ] a self-reported test for the screening of mental disorders in a non-psychiatric setting). METHODS A consecutive series of 2,040 (mean age 51 +/- 13 years) male patients with sexual dysfunction was studied. MAIN OUTCOME MEASURES Several hormonal and biochemical parameters were investigated, along with SIEDY and the MHQ. RESULTS Higher prolactin was observed only in patients using SSRIs, whereas no other hormonal difference was found after adjustment for confounders. Use of SSRIs was associated with a twofold risk for patient hypoactive sexual desire and with a higher impairment of reported erectile function. However, no difference in penile blood flow was observed. A very high risk (sevenfold) for delayed ejaculation (DE) was observed in SSRI users. Interestingly, the association with the mild, but not severe, form of DE was observed also in subjects using non-SSRI antidepressants (3.35 [1.48-7.59]; P < 0.005). Different life stressors and relational parameters were also associated with SSRI use. SSRI users reported less enjoyment with masturbation and decreased partner desire and climax. Conversely, a lack of significant association was observed among BDZ or non-SSRI antidepressant users and all the aforementioned life-stressors and relational parameters. CONCLUSIONS SSRIs can negatively affect all the steps of the male sexual response cycle (desire-arousal-excitement-orgasm). SSRI-associated sexual dysfunction has a deleterious effect on both auto- and couple-erotic performances. Conversely, other antidepressants and BDZ are less often associated with sexual impairment.